Discovery of Pyrazolo[1,5-a]pyrimidine TTK Inhibitors: CFI-402257 is a Potent, Selective, Bioavailable Anticancer Agent

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• 作者：Yong Liu ; Radoslaw Laufer ; Narendra Kumar Patel ; Grace Ng ; Peter B. Sampson ; Sze-Wan Li ; Yunhui Lang ; Miklos Feher ; Richard Brokx ; Irina Beletskaya ; Richard Hodgson ; Olga Plotnikova ; Donald E. Awrey ; Wei Qiu ; Nickolay Y. Chirgadze ; Jacqueline M. Mason ; Xin Wei ; Dan Chi-Chia Lin ; Yi Che ; Reza Kiarash ; Graham C. Fletcher ; Tak W. Mak ; Mark R. Bray ; Henry W. Pauls
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：July 14, 2016
• 年：2016
• 卷：7
• 期：7
• 页码：671-675
• 全文大小：387K
• 年卷期：0
• ISSN：1948-5875

文摘

This work describes a scaffold hopping exercise that begins with known imidazo[1,2-a]pyrazines, briefly explores pyrazolo[1,5-a][1,3,5]triazines, and ultimately yields pyrazolo[1,5-a]pyrimidines as a novel class of potent TTK inhibitors. An X-ray structure of a representative compound is consistent with 1¹/b>2b> type inhibition and provides structural insight to aid subsequent optimization of in vitro activity and physicochemical and pharmacokinetic properties. Incorporation of polar moieties in the hydrophobic and solvent accessible regions modulates physicochemical properties while maintaining potency. Compounds with enhanced oral exposure were identified for xenograft studies. The work culminates in the identification of a potent (TTK Kb>ib> = 0.1 nM), highly selective, orally bioavailable anticancer agent (CFI-402257) for IND enabling studies.