Discovery of (S)-1-(1-(4-Chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (GDC-0994), an Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Inhibitor in Early Clinical Development

被引：135

作者：

Blake, James F. ^{[1
]}

Burkard, Michael ^{[1
]}

Chan, Jocelyn ^{[2
]}

Chen, Huifen ^{[2
]}

Chou, Kang-Jye ^{[2
]}

Diaz, Dolores ^{[2
]}

Dudley, Danette A. ^{[2
]}

Gaudino, John J. ^{[1
]}

Gould, Stephen E. ^{[2
]}

Grina, Jonas ^{[1
]}

Hunsaker, Thomas ^{[2
]}

Liu, Lichuan ^{[2
]}

Martinson, Matthew ^{[1
]}

Moreno, David ^{[1
]}

Mueller, Lars ^{[2
]}

Orr, Christine ^{[2
]}

Pacheco, Patricia ^{[2
]}

Qin, Ann ^{[2
]}

Rasor, Kevin ^{[1
]}

Ren, Li ^{[1
]}

Robarse, Kirk ^{[2
]}

Shahidi-Latham, Sheerin ^{[2
]}

Stults, Jeffrey ^{[2
]}

Sullivan, Francis ^{[1
]}

Wang, Weiru ^{[2
]}

Yin, Jianping ^{[2
]}

Zhou, Aihe ^{[2
]}

Belvin, Marcia ^{[2
]}

Merchant, Mark ^{[2
]}

Moffat, John ^{[2
]}

Schwarz, Jacob B. ^{[2
]}

机构：

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

[2] Genentech Inc, 1 DNA Way, San Francisco, CA 94080 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 59卷 / 12期

关键词：

SMALL-MOLECULE INHIBITORS; STRUCTURE-GUIDED DESIGN; 1ST GLOBAL APPROVAL; ACQUIRED-RESISTANCE; CANCER; RAF; CASCADE; POTENT; ERK2; BRAF;

D O I：

10.1021/acs.jmedchem.6b00389

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

The extracellular signal-regulated kinases ERK1/2 represent an essential node within the RAS/RAF/MEK/ERK signaling cascade that is commonly activated by oncogenic mutations in BRAF or RAS or by upstream oncogenic signaling. While targeting upstream nodes with RAF and MEK inhibitors has proven effective clinically, resistance frequently develops through reactivation of the pathway. Simultaneous targeting of multiple nodes in the pathway, such as MEK and ERK, offers the prospect of enhanced efficacy as well as reduced potential for acquired resistance. Described herein is the discovery and characterization of GDC-0994 (22), an orally bioavailable small molecule inhibitor selective for ERK kinase activity.

引用

页码：5650 / 5660

页数：11

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