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
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
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DOI：
10.1021/acs.jmedchem.6b00389
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发表时间：
2016-06-23
影响因子：
7.3
通讯作者：
Schwarz, Jacob B.
中科院分区：
文献类型：
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作者：
Blake, James F.;Burkard, Michael;Schwarz, Jacob B.
细胞外信号调节激酶 ERK1/2 代表 RAS/RAF/MEK/ERK 信号级联中的重要节点，通常由 BRAF 或 RAS 中的致癌突变或上游致癌信号传导激活。虽然临床证明用 RAF 和 MEK 抑制剂靶向上游节点是有效的，但通过重新激活该途径经常会产生耐药性。同时靶向通路中的多个节点（例如 MEK 和 ERK）有望提高疗效并降低获得性耐药的可能性。本文描述了 GDC-0994 (22) 的发现和表征，GDC-0994 是一种口服生物可利用的 ERK 激酶活性选择性小分子抑制剂。
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.