2. Academic Validation
  3. Structure-guided evolution of potent and selective CHK1 inhibitors through scaffold morphing

Structure-guided evolution of potent and selective CHK1 inhibitors through scaffold morphing

  • J Med Chem. 2011 Dec 22;54(24):8328-42. doi: 10.1021/jm2007326.
John C Reader 1,  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 Collins
Affiliations

Affiliation

  • 1 Cancer Research UK Cancer Therapeutics Unit and Division of Structural Biology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK.
PMID: 22111927 DOI: 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.

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