Discovery of potent and selective CDK8 inhibitors from an HSP90 pharmacophore

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• 作者：Kai Schiemann^a ; ^{kai.schiemann@merckgroup.com" class="auth_mail" title="E-mail the corresponding author} ; Auré ; lie Mallinger^b ; Dirk Wienke^a ; Christina Esdar^a ; Oliver Poeschke^a ; Michael Busch^a ; Felix Rohdich^a ; Suzanne A. Eccles^b ; Richard Schneider^a ; Florence I. Raynaud^b ; Paul Czodrowski^a ; Djordje Musil^a ; Daniel Schwarz^a ; Klaus Urbahns^a ; Julian Blagg^b
• 关键词：JMTPOBLXKZZYCU-UHFFFAOYSA-N ; KBXKPZZOWBAGTC-UHFFFAOYSA-N ; ZKGWDQMQMQRGLJ-UHFFFAOYSA-N ; OHNXBYACIOVGBQ-UHFFFAOYSA-N ; MJZXLJIFSOYQOU-UHFFFAOYSA-N ; LZRZCEHXAQZTIA-UHFFFAOYSA-N ; BGVLCUOYRCTJCU-UHFFFAOYSA-N ; UQRFZZAOVZWDSA-UHFFFAOYSA-N ; ZWTOETHVOACJIW-UHFFFAOYSA-N ; DDMBDFURJHEOSG-UHFFFAOYSA-N ; DALLTCCRBXGGIY-UHFFFAOYSA-N ; CISPMBXZQNYLKC-UHFFFAOYSA-N ; UETJKJCLDAZMNX-UHFFFAOYSA-N ; WVZGDHXIWUSKHK-UHFFFAOYSA-N ; MUKGYZFIZLFCGL-IBGZPJMESA-N ; MUKGYZFIZLFCGL-LJQANCHMSA-N ; LCUMHIHAYAXPDL-UHFFFAOYSA-N ; QOHBWKY
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 March 2016
• 年：2016
• 卷：26
• 期：5
• 页码：1443-1451
• 全文大小：3734 K

文摘

Here we describe the discovery and optimization of 3-benzylindazoles as potent and selective inhibitors of CDK8, also modulating CDK19, discovered from a high-throughput screening (HTS) campaign sampling the Merck compound collection. The primary hits with strong HSP90 affinity were subsequently optimized to potent and selective CDK8 inhibitors which demonstrate inhibition of WNT pathway activity in cell-based assays. X-ray crystallographic data demonstrated that 3-benzylindazoles occupy the ATP binding site of CDK8 and adopt a Type I binding mode. Medicinal chemistry optimization successfully led to improved potency, physicochemical properties and oral pharmacokinetics. Modulation of phospho-STAT1, a pharmacodynamic biomarker of CDK8, was demonstrated in an APC-mutant SW620 human colorectal carcinoma xenograft model following oral administration.