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.

中文翻译：

---

（S）-1-（1-（4-氯-3-氟苯基）-2-羟乙基）-4-（2-（（1-甲基-1 H-吡唑-5-基）氨基）嘧啶-的发现4-yl）pyridin-2（1 H）-one（GDC-0994）是早期临床开发中的一种细胞外信号调节激酶1/2（ERK1 / 2）抑制剂。

细胞外信号调节激酶ERK1 / 2代表RAS / RAF / MEK / ERK信号级联反应中的重要节点，通常由BRAF或RAS中的致癌突变或上游致癌信号传导激活。尽管临床上已证明使用RAF和MEK抑制剂靶向上游淋巴结有效，但耐药性通常是通过重新激活该途径而形成的。同时靶向该途径中的多个节点（例如MEK和ERK），有望提高疗效并降低获得性耐药的潜力。本文描述了发现和表征GDC-0994（22），它是一种对ERK激酶活性具有选择性的口服生物可利用的小分子抑制剂。