The RAS-RAF-MEK-ERK signaling cascade is abnormally activated in various tumors, playing a crucial role in mediating tumor progression. As the key component at the terminal stage of this cascade, ERK1/2 emerges as a potential antitumor target and offers a promising therapeutic strategy for tumors harboring BRAF or RAS mutations. Here, we identified 36c with a (thiophen-3-yl)aminopyrimidine scaffold as a potent ERK1/2 inhibitor through structure-guided optimization for hit 18. In preclinical studies, 36c showed powerful ERK1/2 inhibitory activities (ERK1/2 IC₅₀ = 0.11/0.08 nM) and potent antitumor efficacy both in vitro and in vivo against triple-negative breast cancer and colorectal cancer models harboring BRAF and RAS mutations. 36c could directly inhibit ERK1/2, significantly block the phosphorylation expression of their downstream substrates p90RSK and c-Myc, and induce cell apoptosis and incomplete autophagy-related cell death. Taken together, this work provides a promising ERK1/2 lead compound for multiple tumor-treatment drug discovery.

中文翻译：

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作为有效 ERK1/2 抑制剂的新型 (噻吩-3-基)氨基嘧啶衍生物的结构引导发现和临床前评估

RAS-RAF-MEK-ERK信号级联在多种肿瘤中异常激活，在介导肿瘤进展中发挥着至关重要的作用。作为该级联反应终末阶段的关键成分，ERK1/2 成为潜在的抗肿瘤靶点，并为携带 BRAF 或 RAS 突变的肿瘤提供了一种有前途的治疗策略。在这里，我们通过针对命中18 的结构引导优化，鉴定出具有（噻吩-3-基）氨基嘧啶支架的36c是一种有效的 ERK1/2 抑制剂。在临床前研究中，36c显示出强大的 ERK1/2 抑制活性（ERK1/2 IC ₅₀ = 0.11/0.08 nM），并且在体外和体内对携带 BRAF 和 RAS 突变的三阴性乳腺癌和结直肠癌模型具有有效的抗肿瘤功效。36c可直接抑制ERK1/2，显着阻断其下游底物p90RSK和c-Myc的磷酸化表达，诱导细胞凋亡和不完全自噬相关的细胞死亡。总而言之，这项工作为多种肿瘤治疗药物的发现提供了一种有前途的 ERK1/2 先导化合物。