Discovery of a Covalent Inhibitor of KRASG12C (AMG 510) for the Treatment of Solid Tumors

被引：546

作者：

Lanman, Brian A. ^{[1
]}

Allen, Jennifer R. ^{[1
]}

Allen, John G. ^{[1
]}

Amegadzie, Albert K. ^{[1
]}

Ashton, Kate S. ^{[1
]}

Booker, Shon K. ^{[1
]}

Chen, Jian Jeffrey ^{[1
]}

Chen, Ning ^{[1
]}

Frohn, Michael J. ^{[1
]}

Goodman, Guy ^{[1
]}

Kopecky, David J. ^{[1
]}

Liu, Longbin ^{[1
]}

Lopez, Patricia ^{[1
]}

Low, Jonathan D. ^{[1
]}

Ma, Vu ^{[1
]}

Minatti, Ana E. ^{[1
]}

Nguyen, Thomas T. ^{[1
]}

Nishimura, Nobuko ^{[1
]}

Pickrell, Alexander J. ^{[1
]}

Reed, Anthony B. ^{[1
]}

Shin, Youngsook ^{[1
]}

Siegmund, Aaron C. ^{[1
]}

Tamayo, Nuria A. ^{[1
]}

Tegley, Christopher M. ^{[1
]}

Walton, Mary C. ^{[1
]}

Wang, Hui-Ling ^{[1
]}

Wurz, Ryan P. ^{[1
]}

Xue, May ^{[1
]}

Yang, Kevin C. ^{[1
]}

Achanta, Pragathi ^{[2
]}

Bartberger, Michael D. ^{[3
]}

Canon, Jude ^{[2
]}

Hollis, L. Steven ^{[6
]}

McCarter, John D. ^{[4
]}

Mohr, Christopher ^{[3
]}

Rex, Karen ^{[2
]}

Saiki, Anne Y. ^{[2
]}

San Miguel, Tisha ^{[4
]}

Volak, Laurie P. ^{[5
]}

Wang, Kevin H. ^{[7
]}

Whittington, Douglas A. ^{[7
]}

Zech, Stephan G. ^{[6
]}

Lipford, J. Russell ^{[2
]}

Cee, Victor J. ^{[1
]}

机构：

[1] Amgen Res, Dept Med Chem, One Amgen Ctr Dr, Thousand Oaks, CA 91320 USA

[2] Amgen Res, Dept Oncol Res, One Amgen Ctr Dr, Thousand Oaks, CA 91320 USA

[3] Amgen Res, Dept Mol Engn, One Amgen Ctr Dr, Thousand Oaks, CA 91320 USA

[4] Amgen Res, Dept Discovery Technol, One Amgen Ctr Dr, Thousand Oaks, CA 91320 USA

[5] Amgen Res, Dept Pharmacokinet & Drug Metab, One Amgen Ctr Dr, Thousand Oaks, CA 91320 USA

[6] Amgen Res, Dept Discovery Attribute Sci, 360 Binney St, Cambridge, MA 02142 USA

[7] Amgen Res, Dept Mol Engn, 360 Binney St, Cambridge, MA 02142 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 63卷 / 01期

基金：

美国国家卫生研究院;

关键词：

DRUG DISCOVERY; MUTATIONS; GTP;

D O I：

10.1021/acs.jmedchem.9b01180

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

KRAS(G12C) has emerged as a promising target in the treatment of solid tumors. Covalent inhibitors targeting the mutant cysteine-12 residue have been shown to disrupt signaling by this long-"undruggable" target; however clinically viable inhibitors have yet to be identified. Here, we report efforts to exploit a cryptic pocket (H95/Y96/Q99) we identified in KRAS(G12C) to identify inhibitors suitable for clinical development. Structure-based design efforts leading to the identification of a novel quinazolinone scaffold are described, along with optimization efforts that overcame a configurational stability issue arising from restricted rotation about an axially chiral biaryl bond. Biopharmaceutical optimization of the resulting leads culminated in the identification of AMG 510, a highly potent, selective, and well -tolerated KRAS(G12C) inhibitor currently in phase I clinical trials (NCT03600883).

引用

页码：52 / 65

页数：14

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