jm2007326_si_001.pdf (293.06 kB)
Structure-Guided Evolution of Potent and Selective CHK1 Inhibitors through Scaffold Morphing
journal contribution
posted on 2015-12-16, 20:37 authored by John C. Reader, Thomas P. Matthews, Suki Klair, Kwai-Ming
J. Cheung, Jane Scanlon, Nicolas Proisy, Glynn Addison, John Ellard, Nelly Piton, Suzanne Taylor, Michael Cherry, Martin Fisher, Kathy Boxall, Samantha Burns, Michael
I. Walton, Isaac M. Westwood, Angela Hayes, Paul Eve, Melanie Valenti, Alexis de Haven Brandon, Gary Box, Rob L. M. van Montfort, David
H. Williams, G. Wynne Aherne, Florence I. Raynaud, Suzanne A. Eccles, Michelle
D. Garrett, Ian CollinsPyrazolopyridine inhibitors with low micromolar potency
for CHK1
and good selectivity against CHK2 were previously identified by fragment-based
screening. The optimization of the pyrazolopyridines to a series of
potent and CHK1-selective isoquinolines demonstrates how fragment-growing
and scaffold morphing strategies arising from a structure-based understanding
of CHK1 inhibitor binding can be combined to successfully progress
fragment-derived hit matter to compounds with activity in vivo. The
challenges of improving CHK1 potency and selectivity, addressing synthetic
tractability, and achieving novelty in the crowded kinase inhibitor
chemical space were tackled by multiple scaffold morphing steps, which
progressed through tricyclic pyrimido[2,3-b]azaindoles
to N-(pyrazin-2-yl)pyrimidin-4-amines and ultimately
to imidazo[4,5-c]pyridines and isoquinolines. A potent
and highly selective isoquinoline CHK1 inhibitor (SAR-020106) was
identified, which potentiated the efficacies of irinotecan and gemcitabine
in SW620 human colon carcinoma xenografts in nude mice.