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Predicting New Uses – Gold mine or Bigger Haystack? Numedicus (est. 2008) provides collaborative & consultative services to companies seeking expert advice in the area novel uses for existing drugs www.numedicus.co.uk Prediction of New Uses Plenty of known new uses for existing drugs Drugrepurposing.info contains 1759 repurposing links between mechanism and indication, 159 links between compound and indication and 61 links between compound and mechanism -- so-called "off-target" effects What about unknown new uses? Experimental in silico technologies screening retrospective clinical analysis Ontological indication hopping small variation in API clever IP strategies A C B Experimental Methods Molecular modelling Gene profiling Sirota, 2011; compare mRNA expression & disease: led to topiramate/IBD and cimetidine/lung cancer (not new) Iorio, 2011; similar strategy led to fasudil/HD (not new) Screening Keiser, 2011; compares ligand topology Xie, 2011; chemical system biology to deconvolute MoA Rothstein (Johns Hopkins); ceftriaxone/EAAT2/GLT-1/ALS Melior; MLR-1023/T2D/lyn kinase Side effects Campillos, 2011; phenotypic SE comparison shared target Biovista, 2011; pirlindole/MS Retrospective CT analysis, prescription databases In vitro screening In vivo phenotypic screening Human experience analysis Increasing confidence in result Gene profiling Increasing scale of analysis Molecular modelling Hit compound Lead compound Clinical development Ontological approaches Depre ssion FMS COPD Ulcers SNRI Muscarinic antagonist Glycopyrrolate Milnacipran MS Psoriasis NF-kB BG-12 (dimethyl fumarate) Anti-TNF therapy for Immunoinflammatory disease Approved indications Disease Rheumatoid arthritis Psoriatic arthritis Ankylosing arthritis Juvenile rheumatoid arthritis Crohn disease Ulcerative colitis Etanercept Yes Yes Yes Yes No No Infliximab Yes Yes Yes Under investigation Yes Yes Also uveitis, vasculitis Cleveland Clin J Med 2006, 73(3), 251 …But no beneficial clinical effect in other TNF-driven diseases Indication Systemic Inflammatory Response Syndrome Multiple Sclerosis Systemic vasculitis Sjogren’s syndrome Wegener’s granulomatosis Autoimmune inner ear disease COPD Giant cell arteritis Polymyalgia rheumatica Chronic heart failure Pulmonary sarcoidosis Drug Infliximab/etanercept Pubmed ID 15585509 Lenercept Infliximab Infliximab Etanercept Etanercept Infliximab Infliximab Infliximab Infliximab Etanercept 10449104 17360788 15077311 15673801 16151336 17290043 17470830 17470831 12796126 12853521 …despite efficacy in preclinical models Comprehensive DRP? MOU Subtype Genotype Metabolite Formulation Phenotype Pathw ay Isomer COM patent Target Parent Compound Polypharmacology Combination indication Canonical vs non-canonical Route Disease resistant Fractals in DRP – the more we look the more we find Dimethyl fumarate – from fumigant to MS Thalidomide – from mutagen to myeloma Latanaprost – from glaucoma to eyelash growth Conclusions There are plenty of drug repurposing opportunities New ones can derive from knowledge based approaches, or experimental ones Ontological approaches have led to patented products by linking two known relationships and creating an unknown one Further repurposing hypotheses via similarity analysis have varying degrees of predictive certainty (should these be quantitated, and how?) Repurposing possibilities involve multidimensional variation of (at least) API, target, indication & patent: a complete picture may be unachievable
