Drug Repurposing John P. Overington Stratified Medical @johnpoverington Stratified Medical – Deep Learning in Drug Discovery ~1,500 drugs ~1,000,000,000,000,000,000,000 drug-like molecules Drug Disease ~5,000 ‘treated’ diseases ~14,400 diseases (~7,000 rare diseases) Target ~400 drug targets ~19,000 genes in human genome T. Oprea & J.P. Overington (2015) ‘Computational and Practical Aspects of Drug Repositioning’ Drug Repositioning, Repurposing and Reuse, 1, 28-35 DOI:10.1089/drrr.2014.0009 also published in ASSAY and Drug Development Technologies (2015) 13 299-306 DOI:10.1089/adt.2015.29011.tio drrr PMID:26241209 DREL Drug Repurposing • Drug Repurposing – Finding a new clinical use for an approved drug • Drug Rescue – Finding a clinical use for a stalled clinical development stage compound • Phase 2 or beyond – established PK and tolerability, maybe safety and usually a known chemical structure Drug Repurposing Some Will Pay For What Others Pay To Avoid… Bimatoprost Lumigan TM Latisse TM What Drugs Are Already Used For • There is no consistent description of disease and drug linkage – Several classification schemes exist but it is in the physicians, regulators and manufacturers interest to stay silent on the precise diseases – The Drug ‘Label’ is the best guide to allowed use – The best useful scheme though is probably the WHO ATC • Side effects are usually ‘negative’ ones – Manufacturers need to be very careful about off-label promotion The WHO ATC • ATC – Anatomical Therapeutic Chemical Classification – Updates for new drugs and drugs in registration phase – Contains combinations, and some odd things – Often coupled with DDD • DDD is the defined daily dose – typical daily dose for an adult being treated with the drug ATC Level 1 First level • The first level of the code indicates the anatomical main group and consists of one letter. Code Contents A Alimentary tract and metabolism B Blood and blood forming organs C Cardiovascular system D Dermatologicals G Genito-urinary system and sex hormones H Systemic hormonal preparations, excluding sex hormones and insulins J Antiinfectives for systemic use L Antineoplastic and immunomodulating agents M Musculo-skeletal system N Nervous system P Antiparasitic products, insecticides and repellents R Respiratory system S Sensory organs V Various ATC Levels 2 to 5 Second level • The second level of the code indicates the therapeutic main group and consists of two digits. • Example: C03 Diuretics Third level • The third level of the code indicates the therapeutic/pharmacological subgroup and consists of one letter. • Example: C03C High-ceiling diuretics Fourth level • The fourth level of the code indicates the chemical/therapeutic/pharmacological subgroup and consists of one letter. • Example: C03CA Sulfonamides Fifth level • The fifth level of the code indicates the chemical substance and consists of two digits. • Example: C03CA01 Furosemide Selection of Drugs for Repositioning • Product profile can/should be used to restrict set – E.g. Known oral dosing, no safety warnings, low DDI potential, non-irreversible, no controlled substances, no cytotoxics….. • Use a filtered USAN/INN set – Annotated with a few in silico models – E.g. HERG, BBB – ~3,000 ‘high priority’ compounds Prodrugs Are Problematic Other Structural Complexities • • • • • • Tautomers Epimerization Covalent/reactive Active metabolites Hydration Enumeration of stereoisomers… Protein Kinases • Built dataset of clinical stage small molecule protein kinase inhibitors • 33 approved (3 Japan only, 1 China only) • 488 in total – 2-D structures for 68% – many errors in structure assignment in literature – Patents – (claimed) Targets • Implemented a systems pharmacology pipeline to investigate repositioning and resistance profiling Drug Repurposing • On Target – Finding new uses of a drug acting through the originally known target – Literature, omics experiments….. – Positive feature is that it is likely to be compatible with dosing of original drug • Off Target – Finding new uses of a drug acting through a novel or unanticipated target – Docking, fingerprint methods,…. – Drug was not originally optimised for that target, so need to be watchful of dosing Drug Repurposing • Simplest case is to take a library of drugs and screen them in a model assay – We will look at two papers that did just this, both working on neglected diseases Plasma concentration Cp (mg/L) Drug Action % effect 100 75 XC50 ‘efficacy’ target 50 25 2 1 05.11.2015 Master headline Time (hr) Plasma concentration Cp (mg/L) Acute ADRs Primarily Cmax Linked • Cmax can vary greatly due to drug dose and a wide range of environmental and genetic factors • Occurrence and duration of sideeffects appears stochastic XC50 ‘off’ target • Examples • QT prolongation/hERG effects for cisapride – potentially fatal • Blue vision side effect for sildenafil – an inconvenience % effect 100 75 50 25 2 2 05.11.2015 Master headline Time (hr) Pharmacology Spectrum of a Drug Plasma concentration Cp (mg/L) XC50 ADR target 2 3 05.11.2015 As concentration increases, an ever larger number of targets are affected XC50 ‘off’ target ⇥ Higher dosing - more pharmacology, both positive and negative XC50 ‘efficacy’ target Master headline Time (hr) Drug Repurposing • ‘On Target’ – Finding new uses of a drug acting through the originally known target – Literature, transcriptomics/GWAS experiments….. – Positive feature is that it is likely to be compatible with dosing of original drug – Big exception of ‘privileged’ compartments – occular, brain • ‘Off Target’ – Finding new uses of a drug acting through a novel or unanticipated target – Docking, fingerprint methods,…. – Drug was not originally optimized for that target, so need to be very critical of dosing Off Target Effects ‘Not Optimised’ Plasma concentration Cp (mg/L) • Affinity for novel beneficial target is likely to be lower than for ‘on-target’ • Almost certainly non-optimal dosage/pharmacokinetics for new target • Dependent on disease 2 5 05.11.2015 XC50 ‘off’ target Master headline Time (hr) How to Find Out About Drugs • The Prescribing Information (PI)/Summary of Product Characteristics (SPC) is a good place to start – Let’s look at one….. • Wikipedia is good – but confirm things – Abiraterone, Lemborexant,…. Drug Repurposing Practical John Overington – Stratified Medical 3rd November 2015 Product Profile • The pharmaceutical requirements of a drug – Delivery route • Oral, parenteral, topical, inhaled…. – Drug Drug interactions – Differentiation from current therapies • Safety, Cost, Efficacy – Dosing frequency • Every eight hours, every day, every week, every month – – – – – – – Cost of goods Risk of Misuse/Controlled substances Tolerable side effects Safety in pregnant/breastfeeding populations Dose adjustment in pediatric patients Monitoring – specialist use, liver function tests,… … Task • 5 minutes - As a class: Develop a prototypical product profile for a novel antimalarial – Consider dosing, safety, cost of goods, patient population…. • 30 minutes - As small teams: Examine hits from the Yuan paper – Classify dosing, safety, and approval status – Triage drugs to most likely repurposing candidates • 10 minutes – As a class: Select realistic drug repositioning prospects What The Results Should Look Like Aspirin would be….. Some Homework
