Discovery of a Potent and Selective Oral Inhibitor of ERK1/2 (AZD0364) That Is Efficacious in Both Monotherapy and Combination Therapy in Models of Nonsmall Cell Lung Cancer (NSCLC)

The RAS/MAPK pathway is a major driver of oncogenesis and is dysregulated in approximately 30% of human cancers, primarily by mutations in the BRAF or RAS genes. The extracellular-signal-regulated kinases (ERK1 and ERK2) serve as central nodes within this pathway. The feasibility of targeting the RAS/MAPK pathway has been demonstrated by the clinical responses observed through the use of BRAF and MEK inhibitors in BRAF V600E/K metastatic melanoma; however, resistance frequently develops. Importantly, ERK1/2 inhibition may have clinical utility in overcoming acquired resistance to RAF and MEK inhibitors, where RAS/MAPK pathway reactivation has occurred, such as relapsed BRAF V600E/K melanoma. We describe our structure-based design approach leading to the discovery of AZD0364, a potent and selective inhibitor of ERK1 and ERK2. AZD0364 exhibits high cellular potency (IC50 = 6 nM) as well as excellent physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties and has demonstrated encouraging antitumor activity in preclinical models.RAS/MAPK通路（RAS/MAPK pathway）是肿瘤发生的主要驱动通路，约30%的人类癌症中存在该通路失调，其失调主要由BRAF或RAS基因突变引发。细胞外信号调节激酶（extracellular-signal-regulated kinases, ERK1与ERK2）是该通路的核心节点。针对BRAF V600E/K转移性黑色素瘤患者使用BRAF与MEK抑制剂所观察到的临床响应，已证实靶向RAS/MAPK通路的可行性；然而此类治疗常出现耐药现象。尤为重要的是，当RAS/MAPK通路发生重激活（如复发的BRAF V600E/K转移性黑色素瘤）时，ERK1/2抑制或可用于克服对RAF与MEK抑制剂的获得性耐药，具备临床应用价值。本研究阐述了基于结构的设计策略，该策略助力发现了AZD0364——一种强效且高选择性的ERK1与ERK2抑制剂。AZD0364展现出优异的细胞活性（半最大抑制浓度IC50=6 nM），同时具备良好的理化性质以及吸收、分布、代谢、排泄（ADME，英文全称为absorption, distribution, metabolism, and excretion）特性，且在临床前模型中已显示出令人鼓舞的抗肿瘤活性。