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Discovering new drugs in Africa

Defeating Malaria Together

Kelly Chibale PhD FRSSAf

University of Cape Town

Drug Discovery: kissing many frogs before meeting the prince

Identify disease

Identify-validate target

Identify lead

molecules

Optimize lead

molecules

Pre-clinical trials

Clinical trials

Approval & marketing

Drug discovery process

New medicines - guided by structure

Genome:All drug

able targets

ValidateKnock-out organisms

Assay Set-up

Validation

HTSSpecific Target

Deng X et al, J Biol Chem. 284: 26999-7009 (2009)

Booker ML et al, J Biol Chem. in press(2010)

• Rapid progression with validated targets

New medicines: guided by Biology

Chemistry:All available molecules

HTSWhole parasite

Hits to leads

Identify resistance

• 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

Gamo FJ, et al., Nature 465 (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)

Optimizing molecules to be medicinesData used to make additional refinements to the library Use data to refine compound

design using SARs

Example: Aminopyridines a new exciting anti-malarial series

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• 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 50 60

Pla

sma

Co

nce

ntr

atio

n (

µM)

Time (h)

Rat PK profiles for frontrunner after i.v. and p.o. dosing

10

1

0.1

0.01

10 20 30 400

N NH2

R2

R1

• 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

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

Natural Products: African solutions to a global disease

N

O

OH

N

H

O

O OO

O

H H

H

O

O OO

H H

HO

O

HO

O

NCl

HNN

Half life 8 h Half life 278 h

Insoluble Soluble half life <1h

Soluble half life >24h

O

OO

ONH

NH2R

• Clinically characterise products ‘active in man’

• Reconstruct what happens to natural products in the body

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

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

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(a)Electrochemical oxidation approach

(b)CYP450 oxidative metabolism: human & rat liver

microsomes, bactosomes and recombinant CYP450s

CYP1A1

CYP1A2

CYP2B6

CYP2C9

CYP2D6

CYP3A4

CYP2E1

CYP2A6

CYP2C19

Parent cpd metabolites

CYP1A1CYP2C9

In vitro In vitro Generation of MetabolitesGeneration of Metabolites

6.0 7.0 8.0 9.0Time, min

Inte

nsity, cp

s

DC13

21B3

9-10A

Human Liver Microsomes

DC13 + [O]

DC13 – [SIDE CHAIN]

Inte

nsity, cp

sIn

ten

sity, cps O O

MeO

OMe

O

Available Autumn 2011 Further details malariabox@mmv.org

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