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Innovation and Challenges of Drug repurposing
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Maha Saber-Ayad, MBBS, MD, MRCP(UK), FRCP (Edin.)
Professor of Pharmacology,

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College of Medicine, University of Sharjah

DUPHAT 2023
email: [email protected]
A recent story reflecting the old concept:
Drug Repurposing for COVID-19 D
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The emergence of the
COVID-19 pandemic
Early repurposing of
available drugs in the
market could timely save
Using new technologies,
bioinformatics and AI to H
has mandated the mine BIG data provided
instant (re)search for
potential drug
lives, by skipping the
lengthy phases of
preclinical and initial
“theoretically” potential
therapeutic options for A
candidates. COVID-19.
safety studies.
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Repurposing of Antiviral Agents
Repurposing of
Immunomodulators
2023
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Baricitinib – JAK inhibitor
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Dual mechanism of action of baracitinib;
(A) Inhibition of clathrin-mediated endocytosis of the SARS-CoV2
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(B) Inhibition of the JAK-mediate release of pro-inflammatory cytokines
Richardson, P., Lancet 2020.
Saber-Ayad, M., et al.
Pharmaceuticals 2021
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Why is drug repurposing a favorable approach?

• It carries a lower risk of failure, and a faster track.

• It sorts out, at least in part, the problem of rare diseases.
• the costs of bringing a repurposed drug to market is much less,
compared with an estimated cost for a new chemical entity

US$2-3 Billion US$300 million

To repurpose an approved drug for a

To develop a new lead compound new indication
Why is drug repurposing a favorable approach?

• It carries a lower risk of failure.

• It sorts out, at least in part, the problem of rare diseases.
• the costs of bringing a repurposed drug to market is much less,
compared with an estimated cost for a new chemical entity.
• However,
- The regulatory and phase III costs may remain more or less the same
for a repurposed drug as for a new drug in the same indication.
- The substantial savings are mainly in the preclinical and phase I and II
costs.
Selected successful drug repurposing examples

(Stress Urinary
Incontinence)
Selected successful drug repurposing examples

(Multiple
Sclerosis)
Selected examples where drug repurposing failed

Baricitinib in COVID-19?
Approaches of
Repurposing a Medication

Computational Approaches

Experimental Approaches

Pushpakom S, et al., Nat Rev Drug Discov. 2019.

 Computational approaches
Data-driven

Gene Expression Proteomics Genotype Chemical Structure Electronic Health

Records

Formulate the Hypothesis for

drug repurposing
1. Signature matching
• The signature of a drug
could be derived from three
general types of data:
• A. Transcriptomic (RNA),
proteomic or metabolomic
data;
• Drug-disease similarity: relies
on the signature reversion
principle (SRP).
• Using a connectivity map
(cMap).
• Example: using the anti-
convulsant “topiramate” in
obesity.

Subramanian A et al., Cell, 2017

Drug molecular signature
• Connectivity Maps:
• The Connectivity Map (cMap), which was established in 2006 by the Broad
Institute, consists of gene expression profiles generated by dosing of more
than 1,300 compounds in a number of cell lines.
• The cMap information can be considered as a proxy phenotypic screen for a
large number of compounds and has been successfully used to make drug
repurposing predictions for a number of disease conditions.

• Gene Expression Omnibus

• Array Express

Subramanian A et al., Cell, 2017

B. Chemical structure
• Statistics-based cheminformatics approach was undertaken to predict
new targets for 878 FDA-approved small-molecule drugs and 2,787
pharmaceutical compounds.
• Using a similarity ensemble approach (SEA) to evaluate the 2D
structural similarity of each drug to each target’s ligand set, 23 new
drug–target associations were identified.
• Limitations:
• errors in chemical structures.
• physiological effects that exist beyond the structural relationship (for
example, a metabolite of the original drug with a modified structure could be
the active molecule).

Keiser M. et al, Nature, 2009.

C. Adverse Drug Effects
• Using the adverse effect similarity approach identified novel drug–
target relationships for 746 FDA- approved drugs.
• A Unified Medical Language System (UMLS) ontology for medical
symptoms is used for extracting relevant adverse effect profiles from
drug package inserts, then weighing them based on frequency and
scoring the drugs based on adverse effect similarities
• This approach not only confirmed previously known drug–drug pairs
that shared the same protein target, but also identified new shared
targets for many drug pairs.

Campillos M. et al, Science, 2008.

2. Computational molecular docking

• Conventional docking: one target and multiple ligands.

• Inverse docking: several targets and one ligand

Chiang, A. P. & Butte, A. J. Clin. Pharmacol. Ther., 2009.

2. Computational molecular docking
• Using high-throughput computational docking, molecular fit
computations on 3,671 FDA-approved drugs across 2,335 human
protein crystal structures was conducted.
• Mebendazole, an anti-parasitic drug, has the structural potential to
inhibit vascular endothelial growth factor receptor 2 (VEGFR2), a
mediator of angiogenesis; this was also confirmed experimentally.
• Limitations have been greatly overcome!
• 3D structure for some proteins is not yet available.
• Lack of well-curated macromolecular target database.
• Utility of docking algorithm to predict binding affinity is still questionable.
Dakshanamurthy, S. et al. , J. Med. Chem. 2012
3. Genome-wide association studies
• The catalogue of published GWAS traits from the National Human
Genome Research Institute (NHGRI) identified genes that were
associated with a disease trait to be more likely to code for proteins
that are ‘druggable’ or ‘biopharmable’ than the rest of the genome.
• Over 90 individual genes with a GWAS trait were different from the
original drug indication.
• Example: Denosumab (targets RANKL = TNFSF11) in Crohn’s disease.
• Limitation: No insight toward the relationship of the drug to the
pathophysiology of the disease.
Sanseau P. et al., Nat. Biotechnol. 2012
Grover M.P. et al., BMC Med. Genom. 2015
4. Pathway or network mapping
More insight into disease pathophysiology

• Combined genetic variant information arising

from GWAS with tissue-specific functional
interaction networks using a technique termed
network-wide association study (NetWAS) to
identify disease–gene associations much more
accurately than GWAS alone.

Carlin D.E. et al, iScience, 2019

4. Pathway or network mapping
More insight into disease pathophysiology
• Example: Pathway analysis of gene expression data sets from studies involving a
wide range of respiratory viruses in human host infection models identified 67
common biological pathways that may be important in respiratory viral infections.
• Interrogation of these pathways against the DrugBank database identified several
drugs with a potential effect against host-viral targets. These included pranlukast, a
leukotriene receptor 1 antagonist used in asthma, and amrinone, a
phosphodiesterase inhibitor used in the treatment of congestive heart failure.

Biological
Pranlukast Validation
Amrinone
Clinical
DrugBank
Network Pathways: GSEA Trials
database
Carlin D.E. et al, iScience, 2019
5. Retrospective clinical analysis: use of
electronic health records
• Sildenafil in erectile dysfunction
• Aspirin in colorectal cancer
• Raloxifene in breast cancer
• Propranolol in osteoporosis

Ashburn T.T.&Thor K.B., Nat Rev Drug Discov, 2004

US Preventinve Services Task Force, 2017
Cavalla D.&SingalC. Drug Discov Today, 2012
Jensen P.B. et al., Nat Rev Genet, 2012
Novel sources of data for drug repurposing
• Immortalized human cancer cell lines (CCLs)

Multi-omics

personalized cancer therapy

Electronic Health Records-linked large DNA
biobanks
• Advanced sequencing technologies (All of US
program in the US).
• The PIK3CA inhibitor, alplisib, initially
developed as anti-cancer. In addition, it was
effective in a mouse model of PIK3CA-
related overgrowth syndrome (PROS) and
used then in human subjects.

Venot Q et al. Nature, 2018

Keppler-Noreuil K.M. et al. Am J Med Gen, 2014
Approaches of
Repurposing a Medication

Computational Approaches

Experimental Approaches

Pushpakom S, et al., Nat Rev Drug Discov. 2019.

Experimental approaches
• Binding assays to identify target interactions.
• Cellular ThermoStability Assay (CETSA) to analyze targets and off-targets.
• It maps target engagement in cells using biophysical principles ; predicting
thermal stabilization of target proteins by drug-like ligands (with appropriate
cellular affinity).
• Example: confirmation of cellular targets of crizotinib (TKI).
• A major concern about tyrosine kinases is off-target effects: e.g.,Gefitinib can
target more than 20 different protein kinases, as revealed by mass
spectrometry. Binding assays can identify such promiscuity and suggest
developing more selective TKIs, as ligands for more specific targets.
• Repurposing of imatinib (BCR-ABL inhibitor) to treat KIT-driven gastro-
intestinal stromal tumours.

AlShareef A., et al. Sci Rep, 2016

Experimental approaches
• Binding assays to identify target interactions.
• Prolonged exposure to a TKIs will inevitably lead to phenotypic responses in
cancer cells. High throughput direct binding or catalytic assays are used to
generate heat maps of biologically important interactions.
• Interesting findings of a large “kinome” study showed that
• sorafenib and dasatinib have higher affinity to secondary kinase targets than their known
primary target.
• Non-kinase targets of TKIs are recognized (investigated for treating antibiotic-resistant
infections).

AlShareef A., et al. Sci Rep, 2016

Experimental approaches

• Phenotypic Screening
• Zebra fish model was used to evaluate 39 FDA approved medications for use
in tobacco and alcohol dependence. It was found that apomorphine and
topiramate modified nicotine-induced and ethanol-induced behavior in this
model.

Cousin M.A. et al., PLOS ONE, 2014

One drug repurposed to treat more than one disease

• Saracatinib (SRC TKI)

• Alzheimer’s disease (FYN, an SRC family member, triggers AD)
• Analgesic to treat cancer-induced bone pain (SRC is a part of NMDA complex)
• Treat pulmonary lesions of tuberous sclerosis
• Potential antipsychotic
Barriers to drug repurposing
 Patent considerations:
• Off-patent, a new method-of-use (MOU) patent for repurposed medications.
 Regulatory considerations:
• 10 years in EU (plus 2 years if compiled with a pediatric investigation plan),
• 3 years in US for data exclusivity.
 Organizational hurdles in industry:
• Having the new indication outside the core diseases of Pharmaceutical
company.
• Funding
 Challenges of Big Data:
• Complexity of analysis
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Conclusion
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• Drug repurposing is an effective strategy to reduce costs, time
and efforts required for drug development.
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• Computational and Experimental approaches in presence of
high throughput technologies, advanced bioinformatics and
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publicly available data repositories enhanced repurposing
drugs.
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• Biological validation and clinical trials are still required for a
new indication for which a drug is repurposed.
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Selected References
• Ashburn, T. T. & Thor, K. B. Drug repositioning: identifying and developing new uses for existing drugs. Nat. Rev. Drug
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Discov. 3, 673–683 (2004).
• Keiser, M. J. et al. Predicting new molecular targets for known drugs. Nature 462, 175–181 (2009).
• Saber-Ayad, M.; Hammoudeh, S.; Abu-Gharbieh, E.; Hamoudi, R.; Tarazi, H.; Al-Tel, T.H.; Hamid, Q. Current Status of
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Baricitinib as a Repurposed Therapy for COVID-19. Pharmaceuticals 2021, 14, 680.
• Campillos, M., Kuhn, M., Gavin, A. C., Jensen, L. J. & Bork, P. Drug target identification using side-effect similarity.
Science 321, 263–266 (2008).
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• Yang, L. & Agarwal, P. Systematic drug repositioning based on clinical side-effects. PLOS ONE 6, e28025 (2011)
• Sanseau, P. et al. Use of genome-wide association studies for drug repositioning. Nat. Biotechnol. 30, 317–320
(2012).
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• Grover, M. P. et al. Novel therapeutics for coronary artery disease from genome-wide association study data. BMC
Med. Genom. 8 (Suppl. 2), S1 (2015).
• Wang, Z. Y. & Zhang, H. Y. Rational drug repositioning by medical genetics. Nat. Biotechnol. 31, 1080–1082 (2013)
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• US Preventive Services Task Force. Final recommendation statement. Aspirin use to prevent cardiovascular disease
and colorectal cancer: preventive medication. US Preventive Services Task
https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/aspirin-to-
preventcardiovascular-disease-and-cancer (2017).
Force
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• Cavalla, D. & Singal, C. Retrospective clinical analysis for drug rescue: for new indications or stratified patient groups.
Drug Discov. Today 17, 104–109 (2012).
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Selected References
• Venot, Q. et al. Targeted therapy in patients with PIK3CA-related overgrowth syndrome. Nature 558,
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540–546 (2018).
• Alshareef, A. et al. The use of cellular thermal shift assay (CETSA) to study crizotinib resistance in
ALKexpressing human cancers. Sci. Rep. 6, 33710 (2016).
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• Cousin, M. A. et al. Larval zebrafish model for FDAapproved drug repositioning for tobacco dependence
treatment. PLOS ONE 9, e90467 (2014).
• Kremer, S. & Jones, R. Repurposed drugs: second time lucky. Life Sciences Intellectual Property Review
http://www.lifesciencesipreview.com/article/ repurposed-drugs-second-time-lucky (2014).
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• Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A, Doig A, Guilliams T, Latimer J, McNamee C,
Norris A, Sanseau P, Cavalla D, Pirmohamed M. Drug repurposing: progress, challenges and
recommendations. Nat Rev Drug Discov. 2019 Jan;18(1):41-58. doi: 10.1038/nrd.2018.168. Epub 2018
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Oct 12. PMID: 30310233. (WITH IMPORTANT LINKS RELATED TO DIFFERENT TOOLS and RELEVANT
DATABASE).
• Habib, P. T., Saber-Ayad, M. & Hassanein, S. E. In Silico Analysis of 716 Natural Bioactive Molecules Form
Atlantic Ocean Reveals Candidate Molecule to Inhibit Spike Protein  04 February 2021, PREPRINT
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available at Research Square (2021).
• Habib, P. T., Alsamman, A. M., Saber-Ayad, M., Hassanein, S. E. & Hamwieh, A. COVIDier: A Deep-
learning Tool For Coronaviruses Genome And Virulence Proteins Classification (preprint). bioRxiv
(2020).
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• Saber-Ayad M, Saleh MA, Abu-Gharbieh E. The Rationale for Potential Pharmacotherapy of COVID-19.
Pharmaceuticals 2020, 13, 96. 23