Angewandte

Reviews Chemie

International Edition: DOI: 10.1002/anie.201707816

Drug Design German Edition: DOI: 10.1002/ange.201707816

Small Molecules Drive Big Improvements in Immuno-

Oncology Therapies
Bayard R. Huck, Lisa Kçtzner, and Klaus Urbahns*

Keywords:
checkpoint inhibitor ·
combination therapy ·
kinase inhibitors ·
small molecules ·
T-cells

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Immuno-oncology therapies have the potential to revolutionize the From the Contents
armamentarium of available cancer treatments. To further improve
1. A New Era in Oncology 4413
clinical response rates, researchers are looking for novel combination
regimens, with checkpoint blockade being used as a backbone of the 2. The Advantage of Small
treatment. This Review highlights the significance of small molecules Molecules as Combination
in this approach, which holds promise to provide increased benefit to Partners in Immuno-Oncology 4414
cancer patients.
3. Small-Molecule Checkpoint
Inhibitors 4415

1. A New Era in Oncology 4. Kinase Inhibitors 4417

In the last decade, there has been remarkable success in 5. IDO and A2a Inhibitors 4420
applying targeted molecular therapies to the treatment of
cancer. These approaches are typically based on modulating 6. Phoenix from the Ashes:
aberrant signal transduction pathways within the cancer cells. Chemokine Receptor
However, cancer remains one of the leading causes of Antagonists 4421
morbidity and mortality worldwide, with approximately
14 million new cases and 8.8 million cancer-related deaths 7. Epigenetic Modulators 4423
every year. Furthermore, the benefits of these targeted
therapies can often be short lived, as tumor resistance is 8. TLR Modulators and STING
often observed. As such, new oncology treatments are needed Agonists 4423
to provide improved and more sustained benefit to patients.[1]
In the quest to expand and improve the scope of oncology 9. Conclusion 4425
treatments, researchers have attempted to harness the
immune system of the body as a novel approach to fight
cancer. In 1863, Rudolf Virchow detected the presence of
leukocytes in tumors and suggested a causative relationship.[2] cell death in the cancer cell (Figure 1). Under physiological
Today, we know that cytotoxic CD8 + T-cells recognize conditions, the role of checkpoint proteins is to maintain self-
cancer cells through the T-cell receptor/MHC system. Before tolerance and prevent autoimmunity. Cancer cells, however,
the cancer cell is killed, T-cells need to receive a second deregulate the expression of checkpoint proteins and are
confirmatory signal to become activated. This signal is thereby capable of “hijacking” self-tolerance-enabling mech-
mediated by a variety of co-stimulatory and inhibitory anisms within the tumor microenvironment (Figure 2). The
receptors, which are also referred to as checkpoints. In the most prominent checkpoint receptors are programmed cell
final step of immune-mediated tumor-cell eradication, cyto- death protein 1 (PD-1, CD279), cytotoxic T-lymphocyte
toxic T-cells inject a poisonous cocktail composed of various associated protein 4 (CTLA-4, CD152), and programmed
granzymes, granulysin, and perforin to induce programmed death ligand 1 (PDL-1, CD274). PD-1 and CTLA-4 are
mostly found on T-cells and play a role in dampening the
immune response. PD-L1, a ligand of PD-1, is mainly
expressed on cancer cells and induces tolerance. Together
with a multitude of other proteins, these checkpoint receptors

[*] Dr. B. R. Huck, Dr. L. Kçtzner, Dr. K. Urbahns

Healthcare R&D, Discovery Technologies, Merck KGaA
Frankfurter Strasse 250, 64293 Darmstadt (Germany)
E-mail: [email protected]
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201707816.
T 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution Non-Commercial NoDerivs License, which
permits use and distribution in any medium, provided the original
Figure 1. Kiss of death: A cytotoxic T-cell (lower left) attacking work is properly cited, the use is non-commercial, and no
a cancer cell (upper right). Green: actin (immunofluorescence), blue: modifications or adaptations are made.
nuclei (stained with DAPI), red: T-cells (labeled with CellTracker This article is part of the Special Issue to commemorate the 350th
Orange CMRA). Microscope: Zeiss LSM 880 with AiryScan, 63 W /1.4 anniversary of Merck KGaA, Darmstadt, Germany. More articles can
oil. Scale bar (white, lower right): 5 mm. be found at http://doi.wiley.com/10.1002/anie.v57.16.

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Table 1: Approved and marketed antibody checkpoint inhibitors.

Compound (Brand name) Target Originator Approval
ipilimumab (Yervoy) CTLA-4 Bristol-Myers Squibb 2011
pembrolizumab (Keytruda) PD-1 Merck & Co. Inc., Kenilworth, NJ, US 2014
nivolumab (Opdivo) PD-1 Bristol-Myers Squibb 2014
atezolizumab (Tecentriq) PD-L1 Roche/Genentech 2016
avelumab (Bavencio) PD-L1 Merck KGaA, Darmstadt, Germany/Pfizer 2017
durvalumab (Imfinzi) PD-L1 AstraZeneca 2017

constitute molecular elements of the immunological syn-

apse.[3]
Antibodies that target these checkpoint receptors have
proven efficacious as cancer treatments. Indeed, six com-
pounds have been approved by the regulatory agency within
the last six years as a result of their effectiveness in a host of
oncology indications including, skin, and lung cancer
(Table 1).[4]
From a clinical perspective, results of immuno-oncology
checkpoint inhibitors differ from previous standards of care in
that they induce a significant subset of long-term survivors
(Figure 3). These observed “cures” have sparked enthusiasm
among oncologists and the general public.[4, 5]
However, not all patients benefit from checkpoint inhib-
itors and, in addition, immune-based adverse effects are
frequently observed. Thus, there is a renewed focus on
Figure 2. Cooling down the attack: A T-cell is activated through identifying novel oncology treatments that increase the
recognizing a peptide/MHC complex on a tumor cell. The tumor
percentage of patients who benefit, while limiting adverse
escapes immunity by expressing the checkpoint molecule PDL1 and by
producing kynurenine through IDO or adenosine via CD73. Both events. To achieve this goal, the combination of anti-
molecules have immune-dampening effects mediated through the aryl- checkpoint agents with supportive therapies is actively
hydrocarbon receptor and the A2a adenosine receptor, respectively. being explored.[6]

Bayard R. Huck studied Chemistry at Ursi-

2. The Advantage of Small Molecules as Combi-
nus College and graduated with a Bachelor nation Partners in Immuno-Oncology
of Science degree. He subsequently received
a PhD in Organic Chemistry from the Combination therapies are widely regarded as the future
University of Wisconsin-Madison (Professor of modern oncology. For many cancer types, we are likely to
S. H. Gellman). He is currently the Global see a checkpoint inhibitor as a backbone therapy that could
Head of Medicinal Chemistry at Merck be combined with adjunct therapies. Although this strategy is
KGaA, Darmstadt, Germany.
advantageous from an efficacy point of view, researchers are
also mindful of the possible clinical safety implications. One
drawback of antibodies is their long half-life, which results in
a duration of multiple weeks. Thus, side effects cannot be
easily combated once injected into the body. The case of

Lisa Kçtzner studied chemistry at the Julius- Klaus Urbahns studied chemistry at the uni-
Maximilians-University in Wfrzburg. During versities of Kiel and Freiburg. He completed
her MSc, she was a visiting scientist at the his PhD in synthetic organic chemistry from
Trinity College Dublin (Prof. M. O. Senge). the University of Frankfurt am Main (G.
In 2016, she received her PhD in chemistry Quinkert). He started his professional career
from the Max-Planck-Institut ffr Kohlenfor- at Bayer, holding positions in Germany and
schung in Mflheim an der Ruhr and the Japan, before working for AstraZeneca in the
University of Cologne (Prof. B. List). In UK and Sweden. He is currently head of the
2016, she joined Merck KGaA, Darmstadt, Discovery and Development Technologies
Germany as a laboratory head in medicinal department in Merck KGaA, Darmstadt,
chemistry. Germany’s Healthcare R&D unit. He is
a member of the advisory board of the Lead
Discovery Center (LDC) and the Medicines
for Malaria Venture (MMV).

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Figure 4. A schematic concentration/time diagram comparing qualita-

tively the pharmacokinetics of an antibody (b
b) and a small molecule
(c
c). In contrast to antibodies, small molecules have shorter half-
lives and their dosing regimen can be adapted to clinical needs in
a flexible manner.

Figure 3. Lifting the tail: The difference between targeted and

immuno-oncology cancer treatments as illustrated in a schematic
Kaplan–Meier diagram. Targeted therapy (b b) provides benefit to
patients compared to the standard of care (c c), but responses are
rarely durable. Immune therapy (c c, purple) provides a similar
benefit, but with a “long tail”, as a significant portion of the patients
are cured. The aspiration in the oncology field is to enlarge this
fraction of cures through combinations of targeted and immune
therapy treatments (b b, purple).
Figure 5. A molecular model of the PD-1/PD-L1 interaction. Currently,
765 clinical combination studies are being conducted to interrogate
TGN1412, a CD28 superagonist that created disastrous the relevance of this mechanism for human disease. 194 combination
trials involve small molecules.
cytokine storms in healthy volunteers upon injection of
a single intravenous dose, was a painful reminder of the
possibly dramatic nature of these side effects.[7] emphasis on compounds which are currently in clinical
Although small molecules have dominated anticancer combination trials with checkpoint inhibitors (Table 2).[8]
therapies for decades, this therapeutic modality is so far Given the huge number of drug candidates, we focus on the
missing from the reservoir of commercially available most advanced compounds in each category.
immuno-oncology agents.[4] Small molecules benefit from
their ability to cross cellular membranes and other barriers,
thereby reaching intracellular targets. Furthermore, small 3. Small-Molecule Checkpoint Inhibitors
molecules typically have half-lives of less than 24 hours, and
their ability to achieve efficacy after a more convenient oral 3.1. Small-Molecule PD-1/PD-L1 Inhibitors
administration allows for more flexibility within the treat-
ment regimen. Thus, researchers and clinicians can use The development of small-molecule modulators of the
intermittent dosing and “drug holidays” to balance the risk PD-1/PD-L1 interaction have lagged behind the development
of side effects in combination trials (Figure 4). of PD-1 and PD-L1 antibodies. The crystal structure of the
The area of immuno-oncology is advancing rapidly, with murine PD-1/human PD-L1 interaction revealed the overall
many investigators omitting clinical phases to register and binding mode of the PD-1/PD-L1 interaction, and provided
bring medicines to cancer patients more quickly. The number hope for the rationally guided structure-based design of
of clinical combination studies involving anti PD-1/PD-L1 inhibitors of the PD-1/PD-L1 complex.[9] Unfortunately,
agents (Figure 5) has risen dramatically within the last sequence homology between murine PD-1 and human PD-
18 months from 215 (November 2015) to 765 (May 2017). 1 is low, which precluded drug design. Recently, the crystal
The authors are unaware of any other molecular mechanism structure of the human PD-1/human PD-L1 complex was
that is being studied clinically with this intensity. Of relevance solved, which revealed key interactions between the two
to this Review, approximately one quarter of immuno- proteins and identified “hot spots” that can be mimicked with
oncology clinical studies involve small molecules as combi- substances other than antibodies.[10]
nation partners for checkpoint inhibitors.[6b] Efforts to identify non-antibody inhibitors of the PD-1/
This Review summarizes current highlights in the field of PD-L1 complex were initially undertaken with peptide
small-molecule approaches in immuno-oncology, with an mimetics[11] and macrocyclic peptides.[12] Certain molecules

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Table 2: Small molecules currently in immuno-oncology clinical combi- have been identified that mimic the binding motif of PD-
nation trials. 1 and indeed inhibit the PD-1/PD-L1 interaction. Preclinical
studies also reveal antitumor activity of these molecules.
Nonetheless, there has been no clinical evaluation of these
peptide-related molecules.
The evolution from peptide-related molecules to small-
molecule PDL1 inhibitors has recently been reported. The
initial small-molecule inhibitors of the PD-1/PD-L1 interac-
tion were identified by researchers at Bristol Myers Squibb
(BMS).[13] A homogeneous time-resolved fluorescence
(HTRF) binding assay has shown that compound 1 directly
binds PD-L1 (Figure 6). An X-ray structure analysis revealed
that this molecule binds to PD-L1 in the PD-1 binding pocket.
Its mechanism of action seems to involve the induction of PD-
L1 dimerization, thereby occluding the PD1 interaction
surface.[14]

Figure 6. A small-molecule inhibitor of the PD-1/PD-L1 complex.

A second reported example of small molecules that

disrupt the PD-1/PD-L1 interaction comes from researchers
at Aurigene. In a recent patent application, the inventors
highlight 1,3,4-oxadiazoles 2 and 1,3,4-thiadiazoles 3
(Figure 7).[15] There is speculation that these or related
derivatives have been the subject of a reported license
agreement with Curis.

Figure 7. Small-molecule inhibitors of the PD-1/PD-L1 complex.

Recently, Curis provided details on two small molecules,

CA-170 and CA-327, which can disrupt the PD-1/PD-L1
complex. CA-170 is a dual PD-L1 and VISTA antagonist with
activities of 17 nm and 37 nm, respectively. The compound
potently and selectively rescues human T-cell activation.[16] In
a dose-dependent manner, CA-170 activates T-cells inhibited
by exogenous PD ligands or VISTA, with a similar depth of
response as observed for anti-PD-1 or anti-VISTA antibodies.
Interestingly, there was no rescue of T-cells of other immune
checkpoints, namely, CTLA-4, TIM3, or LAG3. CA-170 is
orally bioavailable and displays dose-proportional exposure
up to 1000 mg kg@1. Antitumor activity was observed in vivo
in immunocompetent mice, with an efficacy similar to that of

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an anti-PD-1 antibody. Interestingly, there was no efficacy cells leads to enhanced cytotoxic T-cell function and restricts
observed in immune-deficient mice. CA-170 is currently tumor growth.[21] Currently, idelalisib is being evaluated in
under evaluation in a first phase I clinical study in humans.[17] combination with pembrolizumab in indications where idela-
Clinical results for CA-170 will shape the evaluation of lisib is already approved, including CLL and B-cell lympho-
whether small molecules offer improvements over the mas.[22]
approved PD-1 and PD-L1 antibodies.
CA-327 selectively and potently inhibits PD-L1 and 4.1.2. PI3Kg Inhibitors
TIM3.[18] In a dose-dependent manner, CA-327 activates T-
cells inhibited by exogenous PD ligands or TIM3, with PI3Kg plays an important role in the function and
a similar depth of response as observed for anti-PD-1 or anti- migration of immune cells, as well as supporting the function
TIM3 antibodies. CA-327 is orally bioavailable across multi- of myeloid cells in the tumor microenvironment.[23] In tumors,
ple preclinical species and inhibits tumor growth in immuno- PI3Kg is activated to promote myeloid cell recruitment and
competent mice. The structures of CA-170 and CA-327 have tumor progression.[24] In models with inactivated PI3Kg,
not been disclosed. reduction in tumor growth is observed due to abrogation of
myeloid cells. Thus, pharmacological inhibition of PI3Kg may
suppress inflammation, growth, and metastasis of tumors.
4. Kinase Inhibitors IPI-549 (5, Infinity) is an orally available, selective PI3Kg
inhibitor (Figure 9).[25] Preclinical data in solid tumor models
4.1. PI3K Pathway—PI3Kd and PI3Kg reveal that IPI-549 targets immune cells and alters the
immune-suppressive microenvironment, thereby promoting
The phosphoinositide-3-kinases (PI3K) are a family of an antitumor immune response that leads to inhibition of
lipid kinases which catalyze the phosphorylation of the 3’- tumor growth. Additionally, in preclinical models, IPI-549
hydroxy group of phosphatidylinositol.[19] This transformation combined with an anti-PD-1 agent leads to enhanced
mediates receptor signaling, contributes to cell growth and inhibition of tumor growth.[26]
development, and is implicated in cell survival. The PI3K
family can be categorized into three classes, with the best
studied being the class I PI3Ks. Class Ia PI3Ks include PI3Ka,
PI3Kb, and PI3Kd, which are activated by receptor tyrosine
kinases, G-protein coupled receptors (GPCRs), and certain
oncogenes. Class Ib PI3Ks include PI3Kg, which is activated
by GPCRs. PI3Kd and PI3Kg are expressed strictly in
immune and hematopoietic cells and are, therefore, of
interest for the treatment of cancer.[20] PI3K inhibitors have
been studied for many years, but their clinical use seems to be
limited by side effects. The opportunity to combine these
agents with checkpoint inhibitors offers new possibilities for
these compounds, raising hope that therapeutic windows can
be enhanced.
Figure 9. The PI3Kg inhibitor IPI-549 (5).

4.1.1. PI3Kd Inhibitors

As the only selective PI3K-g inhibitor in clinical develop-
PI3Kd plays a role in B-cell proliferation and differ- ment, IPI-549 has the potential to offer a unique approach to
entiation, and is often overexpressed in B-cell malignancies. the field of immuno-oncology therapies. IPI-549 is being
As such, PI3Kd is viewed as an interesting oncology target. evaluated in a phase I clinical study, in which the combination
Indeed, multiple PI3Kd inhibitors are under evaluation in of IPI-549 with nivolumab is being investigated in a variety of
clinical studies for the treatment of B-cell malignancies. An cancer indications.[26, 27]
important example is idelalisib (4, Calistoga/Gilead, Figure 8)
which was approved by the FDA for
the treatment of several B-cell 4.2. TGFb Kinase Inhibitors
malignancies, including chronic
lymphocytic leukemia (CLL), fol- The transforming growth factor b (TGFb) signaling path-
licular lymphoma (FL), and small way is complex and results in either tumor-suppressor or
lymphocytic lymphoma (SLL). tumor-promoting activity depending on the cellular context.
Recent preclinical data suggest The tumor-suppressor function of TGFb is lost during cancer
that inhibition of PI3Kd may play progression, which leads to proliferation of tumor cells.[28]
a role in immuno-oncology, as Preclinical studies reveal the utility of TGFb inhibition for the
PI3Kd is required for the immuno- treatment of cancer.[29] Indeed, the small-molecule TGFb
Figure 8. The PI3Kd suppressive function of regulatory inhibitor galunisertib (6, Eli Lilly) is currently in phase II
inhibitor idelalisib (4). T-cells. Inhibition of PI3Kd in T-reg clinical studies in hepatocellular carcinoma (Figure 10).

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Figure 10. The TGFb inhibitor galunisertib (6).

Figure 11. The BTK inhibitors ibrutinib (7) and acalabrutinib (8).
In the context of the immune system, TGFb exerts
systemic immune suppression and inhibits immune surveil-
lance. Furthermore, in the tumor microenvironment, TGFb
regulates the infiltration of immune cells and cancer-associ- provide some clarity on the therapeutic impact of ITK
ated fibroblasts. In preclinical models, pharmacological inhibition.
inhibition of TGFb drives immune activation, including Preclinical data reveal that the combination of ibrutinib
synergy with other immunotherapeutic agents.[30] Galuniser- with an anti-PD-L1 antibody provides improved benefit
tib is being investigated in clinical studies with checkpoint compared to either molecule alone.[34] Interestingly, the
inhibitors, that is, durvalumab for pancreatic cancer and combination benefit was not only observed in lymphomas,
nivolumab for hepatocellular carcinoma and NSCLC.[31] but in solid tumors (breast cancer and colon cancer) where
monotherapy treatment of ibrutinib is not effective, thus
indicating that the combination may significantly increase the
4.3. Bruton’s Tyrosine Kinase (BTK) and Interleukin-2-Inducible indication reach.
Kinase (ITK) Inhibitors Both BTK inhibitors are being evaluated in clinical
studies with checkpoint inhibitors. Ibrutinib is being eval-
BrutonQs tyrosine kinase (BTK) and interleukin-2-indu- uated together with nivolumab against CLL and NHL, and
cible kinase (ITK) are members of the TEC family of kinases, with durvalumab against lymphoma,[35] while acalabrutinib is
which also includes TEC, BMX, and RLK. Members of the under evaluation with pembrolizumab against NSCLC,
TEC family of kinases are primarily expressed in the H&NC, bladder cancer, pancreatic cancer, and ovarian
hematopoietic system and are involved in signaling of the cancer.[36]
antigen receptor. BTK is an integral component of the B-cell
receptor signal transduction pathway and is responsible for
the regulation of B-cell proliferation and survival.[32] BTK 4.4. VEGF Inhibitors
propagates B-cell signaling and is crucial for the maintenance
of humoral immunity and myeloid cell function. Dysregula- Vascular endothelial growth factor (VEGF) is a signal
tion of BTK is linked to B-cell malignancies. ITK is the T-cell- protein that stimulates angiogenesis, that is, the formation of
dominant member of the TEC family of kinases, and is new blood vessels. Cancers that express VEGF are able to
responsible for driving proximal T-cell receptor signaling.[33] grow and metastasize. Not surprisingly, this is a highly sought
Ablation of ITK subverts Th2 immunity, thereby potentiating after drug target.[37] A host of small-molecule VEGF inhib-
Th1-based immune responses. ITK is crucial for regulating T- itors have been identified and approved for renal cell cancer
cell differentiation, and inhibition of ITK leads to the and a small subset of other indications: sunitinib (11, Sugen/
generation of TH1 cells. Inhibition of ITK may shift the Pfizer), sorafenib (10, Bayer), axitinib (9, Pfizer), lenvatinib
balance between Th1 and Th2 T-cells and lead to an (12, Eisai), and pazopanib (13, Glaxo SmithKline)
enhancement in antitumor immune responses. Given their (Figure 12).
biological relevance, both BTK and ITK have drawn atten- Inhibitors of VEGF may also find utility in combination
tion as oncology targets. with immuno-oncology agents, as antiangiogenic therapies
As a consequence of the influence of BTK and ITK on are associated with positive immunological changes because
hematopoietic malignancies, inhibitors of these kinases are of their ability to normalize aberrant tumor vasculature.
under intense evaluation in clinical settings. The most Specifically, VEGF inhibitors increase the number of intra-
developed examples of these molecules include ibrutinib (7, tumoral effector T-cells and reduce the accumulation of
Pharmacyclics/Janssen) and acalabrutinib (8, Acerta, immunosuppressive regulatory T-cells.[38] Not surprisingly,
Figure 11). Ibrutinib is an irreversible inhibitor of BTK and multiple clinical studies are underway that evaluate VEGF
ITK, as well as other kinases, and has been approved for use inhibitors in combination with either anti-PD-1 or anti-PD-L1
against leukemia, mantle cell lymphoma, and Waldenstrom agents. Positive combination benefits have been observed
macroglobulinaemia. Acalabrutinib is reported to be a selec- with several of the combination partners in advanced clinical
tive BTK inhibitor and is currently in phase III clinical studies.[39]
studies. As an ITK-sparing molecule, acalabrutinib may

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Defactinib is currently in clinical evaluation with multiple

checkpoint inhibitors, including pembrolizumab and avelu-
mab.[41]

4.6. MAPK Pathway—MEK and B-Raf Inhibitors

The kinases MEK and B-Raf are both members of the

mitogen-activated protein kinase (MAPK) pathway. As
a result of the role of MAPK signaling and its impact on
tumorigenesis, the pathway has been heavily evaluated in the
search for inhibitors of nodes of the pathway, which may have
an impact on tumor growth. Inhibition of the MAPK signaling
pathway by MEK inhibition, B-Raf inhibition, or a combina-
tion of both has been an effective strategy for the treatment of
metastatic tumors bearing BRAF mutations.[42] Several MEK
inhibitors have been approved, including trametinib (15,
GSK) and cobimetinib (17, Exelixis/Roche), while binimeti-
nib (19, Array) is currently under evaluation in several
phase III clinical studies (Figure 14). In addition, multiple B-
Raf inhibitors have been approved including, dabrafenib (16,
GSK) and vemurafenib (18, Plexxikon/Roche), while encor-
afenib (20, Novartis/Array) is currently in multiple phase III
studies. Furthermore, the combination of a MEK inhibitor
and a B-Raf inhibitor has superior efficacy than either agent
alone. Indeed, the combination of trametinib with dabrafenib,
Figure 12. The VEGF inhibitors axitinib (9), sorafenib (10), sunitinib as well as the combination of cobimetinib with vemurafenib,
(11), lenvatinib (12), and pazopanib (13). have been approved for treating BRAF-mutated metastatic
melanoma.

4.5. FAK Inhibitors

Focal adhesion kinase (FAK) is overexpressed in many

tumors, especially those with a high degree of metastasis. The
role of FAK is implicated in cell motility, invasion, and
survival. Furthermore, FAK has been shown to be an
important regulator of the immunosuppressive tumor micro-
environment, which has been shown to limit the clinical
benefit of immunotherapy.
Defactinib (14, Pfizer) is a well-studied FAK inhibitor
(Figure 13). It is currently in clinical evaluation for a number
of indications, including mesothelioma. Although defactinib
may not have much utility in a monotherapy setting,
preclinical studies reveal defactinib to improve immune
imbalance in the tumor microenvironment and improve
efficacy when combined with checkpoint inhibitors.[40]

Figure 14. The MEK inhibitors trametinib (15), cobimetinib (17), and
binimetinib (19); the B-Raf inhibitors dabrafenib (16), vemurafenib
Figure 13. The FAK inhibitor defactinib (14). (18), and encorafenib (20).

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The MAPK pathway is also involved in T-cell-receptor

signaling. Inhibition of the MAPK pathway leads to enhanced
T-cell activation. MEK inhibitors potentiate antitumor
immunity by inducing expansion of antigen-specific CD8 +
T-cells, which leads to an enhanced antitumor effector T-cell
response.[43] In vivo preclinical studies reveal a combination
benefit with trametinib and an anti-PD-1 agent. Interestingly,
the initial administration of the MEK inhibitor alone followed
by a combination of the MEK inhibitor and an anti-PD-
1 agent was superior to the initial administration of the anti-
PD-1 agent. As a result of the positive preclinical outcomes,
multiple clinical studies are underway that are evaluating
MAPK pathway inhibitors in combination with a checkpoint
inhibitor. Initial results of the combination of cobimetinib and
atezolizumab reveal that the combination is well-tolerated
and active in patients with colorectal cancer.[44] The surprising
immune-potentiating effects of MEK inhibitors offer the
opportunity to combine them with checkpoint inhibitors and
thereby broaden their therapeutic utility towards cancer types
beyond melanoma.

5. IDO and A2a Inhibitors Figure 15. The IDO inhibitors epacadostat (21), EOS-200271 (22),
navoximod (23 a) and indoximod (23 b), and BMS-986205 (24).
5.1. IDO

The depletion of tryptophan and indoleamine results in trations. Indoximod is believed to merely inhibit downstream
immunosuppressive effects in the tumor microenvironment. tryptophan catabolism, thereby relieving the autophagic
Indoleamine-2,3-dioxygenase 1 (IDO-1), a porphyrin-con- response induced by tryptophan deprivation.[51] A final
taining oxidoreductase, catalyzes the degradation of l-tryp- example of a clinically relevant IDO inhibitor is EOS-
tophan to N-formylkynurenine and, therefore, controls 200271 (22, PF-06840003, Pfizer/iTeos). This agent is in
a major pathway of tryptophan catabolism. As IDO is phase I clinical trials for the treatment of patients with
overexpressed in tumors, the inhibition of IDO so as to grade IV glioblastoma or grade III anaplastic glioma.[52]
restore tryptophan levels could be a principle target in
immuno-oncology.[45]
Given the potential clinical impact of this pathway, almost 5.2. Adenosine Receptor Inhibitors
any company active in the immuno-oncology field will try to
develop an IDO inhibitor as part of its immuno-oncology Extracellular adenosine reaches micromolar levels in the
portfolio. The recent acquisition of Flexus pharmaceuticals by tumor microenvironment and results in tumor-promoting
BMS illustrates the excitement in this area: BMS paid effects. Adenosine blocks the activation of immune cells and
800 million US$ upfront and 470 million US$ in milestones, increases the number of regulatory T-cells through activation
mainly to purchase the companyQs preclinical IDO asset, of the A2a and also the low-affinity A2b adenosine recep-
F001287. BMS-986205 (24) is an IDO inhibitor with single- tor.[53] The A2a receptor has been investigated for many years
digit nanomolar cellular potency and is in phase I/II clinical in the area of ParkinsonQs disease; however, no clinical asset
trials.[46] has reached the market. Meanwhile, high expression levels of
Currently, there are multiple IDO inhibitors in clinical both A2a and A2b receptors in the tumor microenvironment
development. Epacadostat (21, Incyte) is the most advanced have sparked the interest of oncologists and medicinal
molecule and is in numerous clinical combination trials with chemists alike (Figure 16).[54] Although caffeine (25) is
anti-PD1 agents such as pembrolizumab and atezolizumab a weak and unspecific antagonist of all adenosine receptor
(Figure 15).[47] In 2016, “orphan drug” designation was subtypes, modern agents have significantly different struc-
assigned to the compound in the USA for the treatment of tures and specificities to caffeine.[55] Some companies decided
stage IIB–IV melanoma.[48] With 17 clinical trials identifiable to in-license A2a receptor antagonists such as vipadenant (27,
in the NIH database, epacadostat is the most investigated Juno/Vernalis) and repurpose them for immuno-oncology.[56]
small-molecule drug in the immuno-oncology space.[49] Preladenant (29, SCH 420815, MK3814, MSD) has also taken
The tricyclic IDO inhibitor navoximod (23 a, NewLink on a second life as a cancer compound after its discontinua-
Genetics) is from a structurally unrelated class of molecules tion in the treatment of ParkinsonQs disease. The compound is
and is in phase I clinical trials.[50] NewLink Genetics is also now in early combination trials with pembrolizumab.[57]
investigating indoximod (23 b), which is a direct inhibitor of Recent discovery efforts have yielded a new wave of A2a
neither IDO nor TDO at relevant pharmaceutical concen- inhibitors. CPI-444 (28, Corvus) is an isoform-selective A2a

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receptors can be expressed on immune cells, endothelial cells,

as well as tumor cells and belong to the class of G-protein-
coupled receptors.[8] So far, about 20 chemokine receptors and
50 ligands have been reported.[8, 63] Initially appreciated as
essential mediators of immune-cell migration, chemokines
are now known to also be involved in non-immune cell
processes which are important for tumor growth and pro-
gression, such as the induction of proliferation or prevention
of apoptosis in cancer cells. Moreover, they can induce the
movement of tumor cells, which is necessary for metastasis.
Chemokines also affect tumor stromal cells and are involved
in the release of growth and angiogenic factors from cells in
the tumor microenvironment, thus having an indirect effect
on tumor growth.[62b] The inhibition of chemokine receptors
can prevent infiltration of macrophages or spread of meta-
stasis and can induce the arrest of tumor growth or apoptosis.
However, despite all efforts in the investigation of chemokine
inhibitors in cancer research, there is currently no small
molecule approved by regulatory agencies for the treatment
of cancer. As a consequence of the large number of different
chemokine receptors and ligands (CXC, CC, XC, and CX3C
subfamilies), the following section will highlight only some
selected examples in the context of immune-oncology.

6.1. CXCR2 Inhibitors

The CXC chemokine receptor CXCR2 is upregulated in

a variety of different tumor cell types and involved in the
proliferation and progression of tumor cells. It is located in
Figure 16. The A2a inhibitors AZD4635 (26), vipadenant (27), CPI-444 the tumor microenvironment and regulates the movement of
(28), preladenant (29), and caffeine (25). immune cells. It was recently reported that genetic ablation or
inhibition of CXCR2 led to reduced metastasis and decreased
inhibitor that demonstrates 55-fold selectivity over A1 and tumorigenesis. It was also shown that CXCR2 signaling can
400-fold selectivity against the A2b and A3 receptors. Initial promote pancreatic tumorigenesis and plays an essential role
clinical data for CPI-444 have recently been disclosed and in the metastasis of pancreatic cancer, thus rendering CXCR2
reveal that the molecule is well-tolerated at a clinical dose of a promising cancer target.[64]
100 mg, with clinical activity as a single agent and in Moreover, CXCR2 inhibition is believed to enhance the
combination with atezolizumab in multiple tumor types.[58] sensitivity to immunotherapies by preventing the attraction of
PBF 509 (Novartis/Palobiofarma; structure not disclosed)[59] myeloid-derived suppressor cells (MDSCs) to tumors.[65]
and AZD4635 (26, HTL 1071, AstraZeneca/Heptares)[60] are AZD5069 (30, AstraZeneca),[66] an antagonist of CXCR2, is
additional A2a antagonists under clinical investigation. currently being investigated in phase Ib/II studies in combi-
AZD4635 is a relatively selective A2a inhibitor with at least nation with the PD-L1 antibody durvalumab for patients with
30-fold selectivity to other adenosine receptors. The agent led advanced solid malignancies as well as metastatic pancreatic
to tumor regression in syngeneic mouse models. AZD4635 is ductal adenocarcinoma (Figure 17). Currently, there are also
in clinical trials against solid tumors and is being investigated plans for a phase I study of the dual CXCR1/2 antagonist SX-
as a single agent and in combination with the PD-L1 blocker 682 (31, Syntrix Biosystems)[67] in combination with pembro-
durvalumab.[61] lizumab for the treatment of metastatic melanoma.[68]

6. Phoenix from the Ashes: Chemokine Receptor

Antagonists

Chemokines are chemotactic cytokines which control the

migratory patterns of immune cells. They play a major role in
the mediation of acute inflammation as well as in the
induction of primary and secondary adaptive immune
responses. Moreover, they are involved in the priming of Figure 17. The CXCR2 antagonist AZD5069 (30) and dual CXCR1/2
naive T-cells and in regulatory T-cell function.[62] Chemokine antagonist SX-682 (31).

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6.2. CXCR4 Inhibitors pembrolizumab for treatment of pancreatic and gastrointes-

tinal cancers[75] as well as with atezolizumab for treatment of
The chemokine receptor CXCR4 is often upregulated in acute myeloid leukemia.[76]
tumor cells and known to be involved in the metastasis of
various cancer types. Binding of the corresponding ligand
CXCL12 (stromal-derived factor-1, SDF-1), leads to stimula- 6.3. CCR2
tion of cell proliferation and survival processes, thereby
promoting tumor growth. The inhibition of CXCR4 dimin- The chemokine receptor CCR2 is mainly expressed on
ishes the proliferation and migration of tumor cells over- monocytes. The binding of the corresponding ligand CCL2
expressing CXCR4. Moreover, it prevents the recruitment of induces chemotaxis, which results in directed migration of
regulatory T-cells and MDSCs to the tumor.[69] monocytes and macrophages to tumor sites.[77] The CCL2-
A plethora of CXCR4 inhibitors have been described;[70] CCR2 axis is important for the recruitment of tumor-
the following will focus on compounds which are clinically the associated macrophages in pancreatic ductal adenocarcinoma
most progressed. and leads to an immunosuppressive tumor microenviron-
The CXCR4 inhibitor plerixafor (32, AMD3100, ment. Further preclinical models also demonstrated that
AnorMED/Genzyme) has already been approved by the blockade of CCR2 can lead to recovery of antitumor
FDA for the treatment of non-Hodgkin lymphoma and immunity.[78] The orally bioavailable CCR2 inhibitor PF-
multiple myeloma (Figure 18). A phase I study for the 4136309 (34, Pfizer, Figure 19) was investigated in a phase I
treatment of chronic lymphocytic leukemia or small lympho-
cytic lymphoma investigated its possible synergistic effects in
combination with rituximab.[71] However, so far, no combina-
tion trial with a checkpoint inhibitor has been reported for
plerixafor.

Figure 19. The CCR2 antagonist PF-416309 (34).

study in combination with the FOLFIRINOX chemotherapy

regimen in patients with borderline resectable and locally
advanced pancreatic adenocarcinoma. The compound was
reported to be safe, and an improvement in tumor response
could be observed.[78, 79] PF-413609 is also being tested in
a phase Ib/II study in combination with Gemcitabine and
Nab-Paclitaxel in first-line metastatic pancreatic patients.[80]
Figure 18. The CXCR4 antagonists plerixafor (32) and X4P-001 (33). Moreover, the CCR2 inhibitor CCX-872 (structure not
disclosed, ChemoCentryx), has been studied in a phase I
clinical trial in combination with FOLFIRINOX in patients
The orally bioavailable CXCR4 inhibitor X4P-001 (33, with advanced nonresectable pancreatic cancer.[81] A further
X4Pharma) has been evaluated in phase I/II studies in phase II study of CCX-872 in combination with an undis-
different solid tumors. In preclinical cancer models, the closed checkpoint inhibitor for pancreatic cancer and pan-
compound reduces tumor growth and increases overall creatic neoplasms is planned to be initiated in 2017.[82]
survival. Currently, clinical trials are investigating the combi-
nation of X4P-001 with nivolumab for the treatment of renal
cell carcinoma[72] and with pembrolizumab in patients with 6.4. CCR5
advanced melanoma.[73]
Several cyclic peptides are also in clinical evaluation as The chemokine receptor CCR5 is expressed by metastatic
CXCR4 inhibitors in combination with checkpoint inhibitors. tumor cells, lymphocytes, and macrophages. The correspond-
LY2510924 (a small cyclic peptide containing non-natural ing ligand CCL5 is produced by T-cells at the invasive margin
amino acids, Eli Lilly) is in a phase I clinical trial in and induces tumor-promoting effects. Inhibition of CCR5 is
combination with durvalumab in patients with solid hypothesized to repolarize tumor-associated macrophages
tumors.[74] BL-8040 (a disulfide-bridged cyclic peptide con- and promote antitumor immunity.[83]
taining non-natural amino acids, BKT140, BioLineRx), is The CCR5-selective inhibitor maraviroc (35, Pfizer),
another cyclic peptide CXCR4 inhibitor that is currently which has already been approved by the FDA for the
under evaluation in numerous clinical combination trials with treatment of HIV, showed promising results in a phase I

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study (MARACON) for the treatment of advanced colorectal HDAC inhibitors influence the immunogenicity of tumors
cancer with hepatic liver metastases (Figure 20). CCR5 by upregulating the expression of NK cell activating ligands,
blockade led to clinical responses in colorectal cancer MHC class I and class II molecules, and proinflammatory
patients, with regression of metastases and changes in the cytokines.[89] In preclinical models, treatment with entinostat
tumor microenvironment without significant side effects.[83, 84] led to a decrease in the number of regulatory T-cells and
suppression of MDSCs.[90] Combination with immune check-
point blockade is expected to suppress evasion of the tumor
immune system even further and activate the adaptive
antitumor immune response. According to this rationale,
multiple HDAC inhibitors are now in clinical evaluation with
checkpoint inhibitors (Table 2).

Figure 20. The CCR5 antagonist maraviroc (35). 8. TLR Modulators and STING Agonists

The activation of the innate immune system can counter-

Moreover, a phase I/II study of a dual CCR2/5 antagonist act tumor-induced immunosuppression and potentially has
BMS-813160 (structure not disclosed, BMS)[85] in combina- a synergistic effect with existing cancer therapies. Toll-like
tion with nivolumab for patients with advanced solid tumors is receptors (TLRs) and stimulator of interferon genes (STING)
envisaged to start in 2017.[86] are therefore promising innate immune targets in cancer
immunotherapy.[91]

7. Epigenetic Modulators
8.1. TLR Modulators
Epigenetic silencing is a frequent event during the
initiation and progression of cancer. Cancers carry mutations Toll-like receptors (TLRs) are type I transmembrane
in genes encoding proteins that epigenetically regulate gene proteins and have a variety of members (TLR 1–13).[92]
expression by modifying DNA and histones.[87] The balance TLRs are expressed in antigen-presenting cells such as
between histone acetylation (HAC) and histone deacetyla- macrophages, B-cells, monocytes, neutrophils, or dendritic
tion (HDAC) is usually well-regulated, but an imbalance is cells, but can also be found on tissues which are exposed to the
frequently observed in tumors.[88] HDAC inhibitors play an external environment, such as, for example, lungs or the
important role in epigenetic regulation, inducing apoptosis, gastrointestinal tract.[93] As a consequence of their ability to
cell-cycle arrest, and cell death. The use of HDAC inhibitors elicit tumor-specific T-cell responses, TLR agonists are
as a therapeutic tool in oncology has been validated, with currently investigated in clinical settings.[94]
approval being granted to vorinostat (36, MK0683, Columbia The majority of clinical trials are based on the use of TLR
University/MSD) for the treatment of cutaneous T-cell agonists as vaccine adjuvants or as a monotherapy, mainly
lymphoma, as well as of chidamide (39, Chenzen Chipscreen) investigating endosomal TLRs which bind nucleic acids such
being given approval in China for treatment of peripheral T- as TLR3, 7, 8, or 9. Whereas the structures of TLR3 and
cell lymphoma. Additional clinical studies of other HDAC TLR9 agonists are mainly based on oligonucleotides, TLR7
inhibitors, including, entinostat (37, Syndax) and mocetino- and TLR8 can be activated by using small molecules as
stat (38, Mirati), are currently ongoing (Figure 21). agonists.[95] The antitumor activity of TLR7 and TLR8
agonists is mainly based on the activation of dendritic cells
and natural killer cells as well as the suppression of regulatory
T-cells.[94a,c, 96] TLR agonists could be applied in combination
therapies with checkpoint inhibitors to trigger a synergistic
effect, alternatively they could be used as therapeutic cancer
vaccine adjuvants to activate dendritic cells.
The TLR7 agonist imiquimod (40, Aldara, Graceway
Pharmaceuticals) is a small-molecule agonist based on an
imidazoquinoline scaffold (Figure 22), and has been approved
as a topical treatment of basal cell carcinoma.[97] Recently, the
compound also showed promising results in a phase II study
for the treatment of bladder cancer.[98] A structurally similar
analogue, resiquimod (41), is a dual TLR7 and TLR8 agonist.
The compound has been well-tolerated as a topical treatment
of actinic keratosis and proved to be even more effective than
imiquimod.[97c] Moreover, it showed promising results in the
Figure 21. The HDAC inhibitors vorinostat (36), entinostat (37), moce- topical treatment of early stage cutaneous T-cell lym-
tinostat (38), and chidamide (39). phoma.[99] The TLR7 agonist 852A (42)[100] and the TLR8

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 Angewandte
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interferons, cytokines, and T-cell recruitment factors

(Figure 24).[8, 107] The STING signaling pathway can be
activated through the binding of small molecules such as
cyclic dinucleotides (CDNs, Figure 25).[108] Whereas cyclic di-
GMP (45) is produced by bacteria, cGAMP (46) is generated
by an endogenous cyclic GMP-AMP synthase (cGAS). The
binding of cGAMP to the STING receptor induces inter-
feron-b expression.[8c, 109]
Figure 22. Imidazoquinoline-based TLR agonists. The structurally unrelated STING activator vadimezan
(47, University of Auckland/Novartis) showed an immune-
mediated antitumor response in mice.[110] Although active in
agonist VTX-2337 (43; Figure 23)[101] are reported to be mice, the compound was found to bind to the human STING
suitable for systemic administration, and have been inves- without activation and failed in a phase III clinical trial in
tigated as single agents for the treatment of solid and combination with chemotherapy for the treatment of
hematological malignancies. The dual TLR7/8 agonist NSCLC.[111]
MEDI9197 (44, MedImmune/LLC) is currently being inves-
tigated in a phase I study as a single agent and in combination
with durvalumab for treatment of solid tumors and cutaneous
T-cell lymphoma (CTCL).[102]

Figure 24. A dendritic cell detects tumor-derived DNA, which often

stems from cancer cells undergoing necrosis. After binding to cyclic
GMP AMP synthase (cGAS), cGAMP is produced which activates
STING, thereby resulting in increased interferon production and T-cell-
priming events in the lymph node. Researchers are trying to identify
synthetic STING agonists to activate this pathway.

Figure 23. The TLR8 agonist VTX-2337 (43) and TLR7/8 agonist MEDI-
9197 (44).

It is important to mention recent studies which have

shown that TLR-induced immunity could also promote,
rather than inhibit, carcinogenesis.[103] Moreover, it has been
reported that chronic low-grade stimulation of TLRs can
prevent tumor apoptosis through the activation of the NF-kB
pathway.[96, 104] This can lead to regulatory T-cell stimulation
and impaired effector T-cells.[8] Additionally, several TLRs
can also be expressed on specific tumor cells and thereby
promote tumor survival.[94a, 105] Thus, it is important to get
a more detailed understanding of TLR-mediated biology in
various cell types to avoid tumor-promoting effects.

8.2. STING Modulators

Stimulator of interferon genes (STING) is expressed in

the endoplasmic reticulum and plays an essential role in
innate immunity. It is expressed in various epithelial and
endothelial cells as well as in haematopoietic cells, including
T-cells, dendritic cells, and macrophages.[106] Activation of the
STING signaling pathway leads to the expression of various Figure 25. Small-molecule STING agonists.

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 Angewandte
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Recent synthetic CDN derivatives feature a chiral phos- pound class for the next generation of immuno-oncology
phothioate group and show increased stability in vivo as well treatments. Small-molecule clinical trial results will be para-
as enhanced activity for the human STING receptor.[108, 112] mount in shaping the promise of this modality in the field of
Interestingly, the R,R derivative 48 showed resistance to immuno-oncology. Of equal importance is the identification
phosphodiesterase degradation, thereby leading to an of novel immuno-oncology-relevant targets that can be
increased level of interferon-b in murine DC2.4 cells, whereas accessed through small-molecule inhibition.
the R,S analogue was comparable to the parent CDN.
Currently, the safety and efficacy of 48 ((R,R)-S2-CDA,
ADU-S100, MIW815; Aduro BioTech/Novartis) is being Acknowledgements
investigated in a phase I clinical trial against advanced/
metastatic solid tumors and lymphomas, administered We gratefully acknowledge Dr. Sakshi Garg, Merck KGaA,
through intratumoral injection.[113] Another study investigates Darmstadt, Germany, who helped with proof-reading the
the combination of ADU-S100 with the anti-PD-1 antibody manuscript and providing the photo for the cover image and
PDR001.[114] The cyclic dinucleotide MK-1454 (structure Figure 1. We also gratefully acknowledge the computational
undisclosed) is also being evaluated in a phase I clinical trial work of Dr. Friedrich Rippmann, Merck KGaA, Darmstadt,
alone and in combination with pembrolizumab.[115] Germany, which resulted in the model of the PD-1/PD-L1
Despite the recent success in the development of STING interaction displayed in Figure 5. We are also grateful to Dr.
agonists in antitumor therapy, an intratumoral injection is Matthias Leiendecker, Merck KGaA, Darmstadt, Germany
necessary to activate the STING receptor efficiently, which for kindly double-checking the accuracy of chemical struc-
may have an impact on the clinical development of this class tures in this article.
of molecules. It is desirable to identify safe and systemically
available STING agonists to treat tumors that are inaccessible
through direct injection. Despite vadimezanQs failure, it is Conflict of interest
encouraging to see that drug-like, non-nucleotide molecules
such as vadimezan exist and work in mice. This bodes well for The authors declare no conflict of interest.
the development of future oral clinical agents with full
agonistic properties. How to cite: Angew. Chem. Int. Ed. 2018, 57, 4412 – 4428
Angew. Chem. 2018, 130, 4499 – 4516

9. Conclusion
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