Fragment Based Drug Discovery - Case Study Examples
Sunday 3rd March 2013
Gordon Saxty
Outline of Talk
• Outline of Examples
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HCS (High Concentration Screening)
Tethering
X-ray
SPR
NMR
• Table of Fragment derived inhibitors
© Astex Pharmaceuticals Inc.
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BrafV600E Example of HCS Screening Vemurafenib (PLX4032)
Bollag et al Nature. 2010 Sep 30;467(7315):596-9
http://practicalfragments.blogspot.co.uk/
© Astex Pharmaceuticals Inc.
PDK-1 Example of Tethering
Erlanson et al Bioorg. Med. Chem. Letts. 21 (10), 3078
© Astex Pharmaceuticals Inc.
http://practicalfragments.blogspot.co.uk
PKB/Akt Example of X-ray Screening
lipophilic
pocket
basic
pocket
GK
NH2
Cl
NH2
Cl
OH
NH2
N N
H
IC50 = 80 μM
LE = 0.47
N N
H
IC50 = 5.2 μM
LE = 0.48
N N
H
IC50 = 0.031μM
LE = 0.49
N N
H
AT13148
Saxty et al J. Med. Chem. 50 (10), 2289, (2007) and 50 (10), 2293, (2007)
Yap et al Clin Cancer Res 18 (2012) 3912-3923
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© Astex Pharmaceuticals Inc.
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p38 Example Using SPR Screening
3hp2
3gcu
1a9u
1kv2
3iw6
1lew
2fsm
Pollack et al J Comput Aided Mol Des
(2011) 25:677–687
© Astex Pharmaceuticals Inc.
Bcl-Xl Example of NMR Screening Navitoclax (ABT 263)
Park et al J. Med. Chem. 51, 6902–6915 (2008)
© Astex Pharmaceuticals Inc.
Approved_________________________________________________________________________
Vemurafenib (PLX4032)
Plexxikon
B-Raf(V600E) inhibitor
Phase 2/3_________________________________________________________________________
MK-8931
Merck
BACE1 inhibitor
Phase 2__________________________________________________________________________
AT13387
Astex
HSP90 inhibitor
Astex
CDK1,2,4,5 inhibitor
AT7519
AT9283
Astex
Aurora, Janus kinase 2 inhibitor
AUY922
Vernalis/Novartis
HSP90 inhibitor
Indeglitazar
Plexxikon
pan-PPAR agonist
Linifanib (ABT 869)
Abbott
VEGF & PDGFR inhibitor
LY2886721
Lilly
BACE1 inhibitor
LY517717
Lilly/Protherics
FXa inhibitor
Navitoclax (ABT 263)
Abbott
Bcl-2/Bcl-xL inhibitor
PLX3397
Plexxikon
FMS, KIT, and FLT-3-ITD inhibitor
Phase 1__________________________________________________________________________
ABT-518
Abbott
MMP-2 & 9 inhibitor
ABT-737
Abbott
Bcl-2/Bcl-xL inhibitor
AZD3839
AstraZeneca
BACE1 inhibitor
AZD5363
AstraZeneca/Astex AKT inhibitor
DG-051
deCODE
LTA4H inhibitor
IC-776
Lilly/ICOS
LFA-1 inhibitor
JNJ-42756493
J&J/Astex
FGFr inhibitor
AT13148
Astex/ICR/CRT
AGC kinase inhibitor
LP-261
Locus
Tubulin binder
LY2811376
Lilly
BACE1 inhibitor
PLX5568
Plexxikon
kinase inhibitor
SGX-393
SGX
Bcr-Abl inhibitor
SGX-523
SGX
Met inhibitor
SNS-314
Sunesis
Aurora inhibitor
Baker M, Nature Reviews Drug Discovery 12, 5-7 (January 2013)
http://practicalfragments.blogspot.co.uk