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Discovering new drugs in Africa
Defeating Malaria Together
Kelly Chibale PhD FRSSAf
University of Cape Town
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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
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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
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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)
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Optimizing molecules to be medicinesData used to make additional refinements to the library Use data to refine compound
design using SARs
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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
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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
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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
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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
9
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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
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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
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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