Transcript slides - Collaborative Drug Discovery

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
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Plenty of known new uses for existing drugs
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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?
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Experimental
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in silico technologies
screening
retrospective clinical analysis
Ontological
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indication hopping
small variation in API
clever IP strategies
A
C
B
Experimental Methods
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Molecular modelling
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Gene profiling
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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
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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
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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
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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