Discovering new drugs in Africa

1. Discovering new drugs in Africa Defeating Malaria Together Kelly Chibale PhD FRSSAf University of Cape Town

2. Drug Discovery: kissing many frogs before meeting the prince Drug discovery process Identify disease Identify-validate target Identify lead molecules Optimize lead molecules Pre-clinical trials Clinical trials Approval & marketing

3. Genome: All drug able targets Validate Knock-out organisms Assay Set-up Validation HTS Specific Target New medicines - guided by structure • Rapid progression with validated targets Deng X et al, J Biol Chem. 284: 26999-7009 (2009) Booker ML et al, J Biol Chem. in press(2010)

4. New medicines: guided by Biology Chemistry: All available molecules HTS Whole parasite Hits to leads • Screening five million compounds • 25’000 hits < 1 uM • Fast track to man – less than four years • Bottle neck: how to optimise them for activity in patients Identify resistance Gamo FJ, et al., Nature465 (7296): 305–310 (2010) Guiguemde WA, et al., Nature 465, 311–315 (2010) Rottman M., et al, Science 325 1175-1180 (2010) Wells TNC Science 329 1153-1154 (2010)

5. Optimizing molecules to be medicines Data used to make additional refinements to the library Use data to refine compound design using SARs

6. Example: Aminopyridines a new exciting anti-malarial series • In vivo P. berghei inhibition (p.o.) 99.5%, > 30 days survival with cures, including 30 mg/kg single dose cure. • Cured all mice in onset and recrudescence assay. No recrudescence observed. • ED90 (single dose, p.o.): 1.74 mg/kg • T1/2 = 7-8 h; BA = 51%@ 20mg/kg 10 1 Rat PK profiles for frontrunner after i.v. and p.o. dosing 0.1 0.01 10 20 30 40 0 50 60 Plasma Concentration (µM) • Exciting new chemical series • Project led from H3-D (Cape Town) supported by TIA and MMV • Single dose cures in mouse models of malaria • Preclinical Candidate expected 1H 2012 Time (h)

7. Success built on the right chemistry • New Hits to leads model pioneered by UCT and MMV • Dedicated teams: medicinal chemists, cell pharmacology • Partnered with South African Technology Innovation Agency • MMV experienced Mentors • Common in vivo centres of excellence

8. Clinically characterise products ‘active in man’ Reconstruct what happens to natural products in the body R Natural Products: African solutions to a global disease Half life 8 h Half life 278 h Insoluble Soluble half life <1h Soluble half life >24h Natural products as starting points for future anti-malarial therapies: going back to our roots? Wells TN Malaria Journal 2011,10:S3. How can natural products serve as a viable source of lead compounds for the development of new/novel anti-malarials? Guantai E, Chibale K Malaria Journal 10:S2

9. Understanding natural products and their metabolism Some molecules have to be metabolised to be active Study in vitro with enzymes to replace liver and gut

10. In vitro Generation of Metabolites • Electrochemical oxidation approach • CYP450 oxidative metabolism: human & rat liver microsomes, bactosomes and recombinant CYP450s CYP 1A1 CYP 1A2 CYP 2B6 CYP 2C9 CYP 2D6 CYP 3A4 CYP 2E1 CYP 2A6 CYP 2C19 metabolites Parent cpd CYP1A1 CYP2C9

11. DC13 21B3 Intensity, cps 6.0 7.0 8.0 9.0 Time, min DC13 + [O] DC13 – [SIDE CHAIN] Intensity, cps 9-10A Intensity, cps Human Liver Microsomes

12. Available Autumn 2011 Further details malariabox@mmv.org

13. Thanks to all our colleagues and partners – but especially to the children and their families who make the next generation of malaria therapy a reality