2,8-Disubstituted-1,6-Naphthyridines and 4,6-Disubstituted-Isoquinolines with Potent, Selective Affinity for CDK8/19

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• 作者：Aurélie Mallinger ; Kai Schiemann ; Christian Rink ; Jimmy Sejberg ; Mark A. Honey ; Paul Czodrowski ; Mark Stubbs ; Oliver Poeschke ; Michael Busch ; Richard Schneider ; Daniel Schwarz ; Djordje Musil ; Rosemary Burke ; Klaus Urbahns ; Paul Workman ; Dirk Wienke ; Paul A. Clarke ; Florence I. Raynaud ; Suzanne A. Eccles ; Christina Esdar ; Felix Rohdich ; Julian Blagg
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：June 9, 2016
• 年：2016
• 卷：7
• 期：6
• 页码：573-578
• 全文大小：447K
• 年卷期：0
• ISSN：1948-5875

文摘

We demonstrate a designed scaffold-hop approach to the discovery of 2,8-disubstituted-1,6-naphthyridine- and 4,6-disubstituted-isoquinoline-based dual CDK8/19 ligands. Optimized compounds in both series exhibited rapid aldehyde oxidase-mediated metabolism, which could be abrogated by introduction of an amino substituent at C5 of the 1,6-naphthyridine scaffold or at C1 of the isoquinoline scaffold. Compounds 51 and 59 were progressed to in vivo pharmacokinetic studies, and 51 also demonstrated sustained inhibition of STAT1^SER727 phosphorylation, a biomarker of CDK8 inhibition, in an SW620 colorectal carcinoma human tumor xenograft model following oral dosing.