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

详细信息    查看全文

• 作者：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 Collins
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：December 22, 2011
• 年：2011
• 卷：54
• 期：24
• 页码：8328-8342
• 全文大小：643K
• 年卷期：v.54,no.24(December 22, 2011)
• ISSN：1520-4804

文摘

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.