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Structure-Guided Evolution of Potent and Selective CHK1 Inhibitors through Scaffold Morphing

Reader, John C., Matthews, Thomas P., Klair, Suki, Cheung, Kwai-Ming J., Scanlon, Jane, Proisy, Nicolas, Addison, Glynn, Ellard, John, Piton, Nelly, Taylor, Suzanne, and others. (2011) Structure-Guided Evolution of Potent and Selective CHK1 Inhibitors through Scaffold Morphing. Journal of Medicinal Chemistry, 54 (24). pp. 8328-8342. ISSN 0022-2623. (doi:10.1021/jm2007326) (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided) (KAR id:58567)

The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided. (Contact us about this Publication)
Official URL
http://doi.org/10.1021/jm2007326

Abstract

Pyrazolopyridine 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.

Item Type: Article
DOI/Identification number: 10.1021/jm2007326
Subjects: Q Science
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Michelle Garrett
Date Deposited: 11 Nov 2016 10:53 UTC
Last Modified: 13 Mar 2020 04:08 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/58567 (The current URI for this page, for reference purposes)
Garrett, Michelle D.: https://orcid.org/0000-0002-3939-1673
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