Lead optimization of purine based orally bioavailable Mps1 (TTK) inhibitors

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• 作者：D. Vijay Kumar^a ; ^{dvijayku@hotmail.com} ; Christophe Hoarau^a ; Matthew Bursavich^a ; Paul Slattum^a ; David Gerrish^a ; Kraig Yager^a ; Michael Saunders^a ; Mark Shenderovich^a ; Bruce L. Roth^b ; Rena McKinnon^b ; Ashley Chan^b ; Daniel M. Cimbora^b ; Chad Bradford^c ; Leslie Reeves^c ; Scott Patton^c ; Damon I. Papac^c ; Brandi L. Williams^b ; Robert O. Carlson^b
• 关键词：Mps1 kinase ; TTK kinase ; Lead optimization ; Cancer ; Kinase selectivity
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：1 July, 2012
• 卷：22
• 期：13
• 页码：4377-4385
• 文件大小：3235 K

摘要

Efforts to optimize biological activity, novelty, selectivity and oral bioavailability of Mps1 inhibitors, from a purine based lead MPI-0479605, are described in this Letter. Mps1 biochemical activity and cytotoxicity in HCT-116 cell line were improved. On-target activity confirmation via mechanism based G2/M escape assay was demonstrated. Physico-chemical and ADME properties were optimized to improve oral bioavailability in mouse.