Discovery of Tetrahydropyridopyrimidines as Irreversible Covalent Inhibitors of KRAS-G12C with In Vivo Activity

被引：79

作者：

Fell, Jay B. ^{[1
]}

Fischer, John P. ^{[1
]}

Baer, Brian R. ^{[1
]}

Ballard, Joshua ^{[1
]}

Blake, James F. ^{[1
]}

Bouhana, Karyn ^{[1
]}

Brandhuber, Barbara J. ^{[1
]}

Briere, David M. ^{[2
]}

Burgess, Laurence E. ^{[1
]}

Burkard, Michael R. ^{[1
]}

Chiang, Harrah ^{[2
]}

Chicarelli, Mark J. ^{[1
]}

Davidson, Kevin ^{[1
]}

Gaudino, John J. ^{[1
]}

Hallin, Jill ^{[2
]}

Hanson, Lauren ^{[1
]}

Hee, Kenneth ^{[1
]}

Hicken, Erik J. ^{[1
]}

Hinklin, Ronald J. ^{[1
]}

Marx, Matthew A. ^{[2
]}

Mejia, Macedonio J. ^{[1
]}

Olson, Peter ^{[2
]}

Savechenkov, Pavel ^{[1
]}

Sudhakar, Niranjan ^{[2
]}

Tang, Tony P. ^{[1
]}

Vigers, Guy P. ^{[1
]}

Zecca, Henry ^{[1
]}

Christensen, James G. ^{[2
]}

机构：

[1] Array BioPharma Inc, 3200 Walnut St, Boulder, CO 80301 USA

[2] Mirati Therapeut Inc, 9393 Towne Ctr Dr,Suite 200, San Diego, CA 92121 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2018年 / 9卷 / 12期

关键词：

Cancer; KRAS; G12C; covalent; KRAS; CANCER;

D O I：

10.1021/acsmedchemlett.8b00382

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

KRAS is the most frequently mutated driver oncogene in human cancer, and KRAS mutations are commonly associated with poor prognosis and resistance to standard treatment. The ability to effectively target and block the function of mutated KRAS has remained elusive despite decades of research. Recent findings have demonstrated that directly targeting KRAS-G12C with electrophilic small molecules that covalently modify the mutated codon 12 cysteine is feasible. We have discovered a series of tetrahydropyridopyrimidines as irreversible covalent inhibitors of KRAS-G12C with in vivo activity. The PK/PD and efficacy of compound 13 will be highlighted.

引用

页码：1230 / 1234

页数：9

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