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New Ideas – New Medicines – New Hope
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iThemba – at a glance
• Mission: To become the premier medicinal chemistry driven drug discovery organization in Africa and to improve African healthcare through, novel, affordable small molecule drugs
• Strategy: leverage the expertise of founders and SAB, generate IP and partner projects with major pharmaceutical companies, offer world class chemistry services to offset drug discovery cash-burn with novel business model
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Business Model
• Offset discovery ‘cash-burn’ by building world class collaborative service business
• Invest profits from above into in-house projects
• Identify, funded, IP generating collaborations
• License products at suitable point
• Retain marketing rights in Africa
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Board of Scientific Advisors
• Prof. Dennis Liotta- Emory University, Atlanta, USA
• Prof. James Bull- University of Cape Town, South Africa
• Prof. Anthony G. M. Barrett- Imperial College, London, United Kingdom
• Prof. Erick Carreira- ETH, Zurich
• Prof. Steven V. Ley- Cambridge University, England
• Dr. George R. Painter- Chimerix Inc., NC, USA
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Drug Discovery
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Disease Focus
Medicinal Chemistry
Drug Discovery
Malaria300-500 million infected p.a. 1-2 million deaths p.a. mostly children
HIV6 million HIV+ in SA alone4 million new infections p.a.Over 30 million HIV+ in Africa
TB8 million infections and 2 million deaths p.a. Mortality growing at 20% p.aResistance
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Pipeline
Proposal Screening Hit to LeadLead
OptimisationProcess
Optimisation
TB/ICL
Malaria hits
Set 1
(12k, Malaria)
Set 1
(7k, TB)Abacavir
IF – TB Nitroimidazoles
Malaria proposals
TB Hits
(NIH/TB CoC)
TB selective macrophage accumulation
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Current Mtb Therapy Outdated
• About 1/3 of the global population is infected with Mycobacterium tuberculosis (Mtb)
• Annually, nearly 8 million of the infected people develop active TB
• Current therapy takes too long to administer
• Current regimen from 1960’s
• 6 – 9 months to complete therapy
• Non-compliance results in drug-resistant strains
• Some resistant strains untreatable
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TB adapts
• Like all pathogens TB adapts to its environment
• Mycobacteria mobilize the glyoxylate shunt for catabolism of fatty acids in order to sustain infection in an immune competent host
• The glyoxylate shunt is unique to bacteria and lower eukaryotes
• IsoCitrate Lyase (ICL) and Maleate Synthase (MS) are key enzymes in this process
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Isocitrate Lyase
• ICL (plus MS) allows MTB to bypass the CO2-generating steps of the tricarboxylic acid (TCA) cycle – The metabolic pathway by which acetate is oxidized to generate ATP.
• The shunt consumes two molecules of acetyl CoA to generate one molecule of succinate. – Lipids are a source of acetyl CoA, and succinate is a precursor for the
synthesis of glucose.
• The net effect is that the glyoxylate shunt allows MTB to synthesize carbohydrates from fatty acids. – Thus, disruption of this pathway is a viable treatment for latent
tuberculosis infections.
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Target Validation
• ICL promotes bacterial survival in infected macrophages
– McKinney et al. Nature, 2000
• Gene deletion results in impaired growth
– McKinney et al. Nat. Med, 2005
• Glyoxylate cycle is essential for TB growth and persistence in macrophages and mice
ICL Previously deemed ‘un-druggable’
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Solution
• Screen a focused set of small molecules against ICL
– 2 x small molecule inhibitors identified (IC50
<50nM)
– Program designed and initiated to address liabilities
– Promising efficacy against Mtb
Technology licensed from Emory University
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Isocitrate Lyase
• Isoniazid and Rifampin like activity
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Novel iThemba Nitroimidazoles• In-house program to discover new nitroimidazoles
• Favourable IP position
• Short synthetic routes using readily available reagents, and established synthetic protocols
• No chiral centres
• Incorporate solubilizing groups, overcoming associated solubility and bioavailability problems
• No structural alerts
• Increased molecular flexibility
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HIV Massive Problem in SA
• South Africa is currently experiencing one of the most severe AIDS epidemics in the world
• At the end of 2007, there were approximately 5.7 million people living with HIV in South Africa, and almost 1,000 AIDS deaths occurring every day
• TB co-infection probably largest killer of HIV positive patients
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iThemba Solution
• Take existing drug and produce for less
• New process for anti-retroviral drug
– 2007 global sales $220 million
– Off patent 2009
– Current synthetic route 15 steps, low yield
– iThemba has licensed technology from Emory university for 7 step process
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Short-circuiting Drug Discovery
• Traditional drug discovery approach not viable in South Africa
– Cost and lack of infrastructure
– Too many hurdles
• Solution to target whole organisms
– Take away major hurdles
– Identify efficacious hits immediately
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• Negotiate use of other companies screening collections
– Requires no target/disease conflicts
• Leverage neglected disease angle
• Requires no capital investment in library purchase and storage
iThemba Approach
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• Novel screening collaborations in place for Malaria (MMV sponsored)
• Medical Research Council Technology• 45k compounds
• Constructed from commercial sources
• Historically good hit rate
• Chimerix compound collection• 7k compounds
• Acquired from Dr Leroy Townsend (University of Michigan)
• Contains numerous unique nucleoside analogues as well as a diverse set of heterocycles
iThemba Screening Solution
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Screening Progress
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• Chimerix collection of nucleoside analogues– 131 cpds with activity IC50<1µM
– High toxicity attrition
– Mitochondrial toxicity flag
– Highly novel structures
• MRCT library diverse heterocyclic structures– Low molecular weight (<300)
– No toxicophores or potential reactive functional groups
– 30 cpds with activity IC50<1µM
– MMV proposal submitted
– Solids re-ordered
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Collaborations
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Chemistry Services
• Services– FTE contracts– Custom Medicinal Chemistry– Custom synthesis/arrays– Individual compound synthesis– Scale up
• Cost-effective and alternative synthetic routes
• Design and synthesis of molecules with drug-like properties
• Hit-to-lead optimization22
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Capabilities
• Provide synthesis on milligram to 50+ gram scale on single or multistep routes
• Follow established synthetic routes, design new synthetic routes, or trouble-shoot existing synthetic routes
• Provide custom intermediate/template or monomer/reagent synthesis
• Prepare analog synthesis• Produce synthesis of metabolites or standards
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Capabilities
• Pharmaceutical standard chemistry
– Fully functional synthesis labs
– ~750m2 of useable laboratory space
• Microwave synthesiser
• Automated prep and analytical HPLC
• Parallel sysnthesis and evaporation
• Pharma-standard analytical capability
– State-of-the-art LC/MS and NMR (400MHz)
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Collaborations, example 1
• Brief: Synthesis of a number of functionalised steroid analogues as potential anti-cancer agents
• Solution: iThemba leveraged expertise on it’s SAB to devise novel routes to desired tool compounds
• Deliverables: 15 synthetic steps, 11 test compounds (>95% purity, ≥25mg) in 5 weeks
• Preliminary Results: 3 examples inhibit cell proliferation in the metaphase with <20nM EC50’s
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Collaborations, example 2
• Brief: Take computational derived fragments from marketed drugs and design library
• Solution: Using in-silico techniques and RO3 100 component library deisgned
• Deliverables: 10, 10 component fragment sets with >95% purity and ≥100mg
• Time frame: 3 months from project initiation
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Why iThemba?
• Competitive cost base
• Strong IP laws in South Africa
• Access to superlative Scientific Advisory Board
• Good cultural fit
• Moral leverage – all profits re-invested into neglected disease research
• Governmental support
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Customer Needs! • Communication
– Dedicated and accessible project leader
• Confidentiality
– Dedicated, backed up server , ELN,
• Quality
• Safety & Environment
– Comply with global standards, PPE culture
• Competitive pricing with flexible terms
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Rates & Contact Information• Competitive rates• Flexible pricing model
– Per FTE– Bid per project– Bid per compound– Bid per chemical step
• Contact: Dr. Chris Edlin– Tel (dir) +27 11 605 2635– Cell +27 82 350 4313– E-mail: [email protected]
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Improving healthcare in Africa and the developing world
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