Structure-guided evolution of potent and selective CHK1 inhibitors through scaffold morphing.
Structure-guided evolution of potent and selective CHK1 inhibitors through scaffold morphing.
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DOI：
10.1021/jm2007326
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发表时间：
2011-12-22
影响因子：
7.3
通讯作者：
Collins, Ian
中科院分区：
文献类型：
--
作者：
Reader, John C.;Matthews, Thomas P.;Klair, Suki;Cheung, Kwai-Ming J.;Scanlon, Jane;Proisy, Nicolas;Addison, Glynn;Ellard, John;Piton, Nelly;Taylor, Suzanne;Cherry, Michael;Fisher, Martin;Boxall, Kathy;Burns, Samantha;Walton, Michael I.;Westwood, Isaac M.;Hayes, Angela;Eve, Paul;Valenti, Melanie;Brandon, Alexis de Haven;Box, Gary;van Montfort, Rob L. M.;Williams, David H.;Aherne, G. Wynne;Raynaud, Florence I.;Eccles, Suzanne A.;Garrett, Michelle D.;Collins, Ian
先前通过基于片段的筛选鉴定了对CHK 1具有低微摩尔效力且对CHK 2具有良好选择性的吡唑并吡啶抑制剂。将吡唑并吡啶优化为一系列有效的和CHK 1选择性的异喹啉证明了如何将基于CHK 1抑制剂结合的结构理解产生的片段生长和支架变形策略结合起来，以成功地将片段衍生的命中物质进展为具有体内活性的化合物。通过多个支架变形步骤解决了改善CHK 1效力和选择性、解决合成易处理性和在拥挤的激酶抑制剂化学空间中实现新奇的挑战，所述多个支架变形步骤通过三环嘧啶并[2，3-B]氮杂吲哚进展为N-（吡嗪-2-基）嘧啶-4-胺并最终进展为咪唑并[4，5-c]吡啶和异喹啉。鉴定了一种有效且高选择性的异喹啉CHK 1抑制剂（SAR-020106），可增强伊立替康和吉西他滨在裸鼠SW 620人结肠癌异种移植物中的疗效。
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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