Transcript Diapositive 1 - Medicines for Malaria Venture (MMV)

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
Drug discovery process
Identify
disease
Identifyvalidate
target
Identify
lead
molecules
Optimize
lead
molecules
Pre-clinical
trials
Clinical
trials
Approval &
marketing
New medicines - guided by structure
Genome:
All drug
able targets
Validate
Knock-out
organisms
Assay
Set-up
Validation
• 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)
HTS
Specific
Target
New medicines: guided by Biology
Chemistry:
All available
molecules
HTS
Whole
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 medicines
Data used to make additional
refinements to the library
Use data to refine compound
design using SARs
• 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
Plasma Concentration (µM)
Example: Aminopyridines a new exciting antimalarial series
Rat PK profiles for frontrunner
after i.v. and p.o. dosing
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0.1
0.01
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10
20
30
40
50
60
Time (h)
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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
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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
Half life 8 h
Half life 278 h
R
Insoluble
Soluble
half life <1h
Soluble
half life >24h
• 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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In vitro Generation of Metabolites
(a) Electrochemical oxidation approach
(b)CYP450 oxidative metabolism: human & rat liver microsomes,
bactosomes and recombinant CYP450s
CYP
1A1
CYP
1A2
CYP
2B6
CYP
2C9
CYP
2D6
metabolites
CYP
3A4
CYP
2E1
CYP
2A6
Parent cpd
CYP1A1
CYP2C9
CYP
2C19
DC1
3
DC13
+ [O]
21B3
MeO
Intensity, cps
DC13 – [SIDE
CHAIN]
O
O
O
OMe
Intensity, cps
9-10A
Intensity, cps
Human Liver
Microsomes
6.0
7.0
Time, min
8.0
9.0
Available Autumn 2011
Further details [email protected]
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