The emergence and evolution of new immunological cancer therapies has sparked a rapidly growing interest in discovering novel pathways to treat cancer. Toward this aim, a novel series of pyrrolidine derivatives (compound 5) were identified as potent inhibitors of ERK1/2 with excellent kinase selectivity and dual mechanism of action but suffered from poor pharmacokinetics (PK). The challenge of PK was overcome by the discovery of a novel 3(S)-thiomethyl pyrrolidine analog 7. Lead optimization through focused structure–activity relationship led to the discovery of a clinical candidate MK-8353 suitable for twice daily oral dosing as a potential new cancer therapeutic.

中文翻译：

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MK-8353：口服可生物利用的双机制ERK肿瘤抑制剂的发现

新的免疫癌症治疗方法的出现和发展引发了人们对发现治疗癌症新途径的兴趣迅速增长。为了实现这一目标，已鉴定出一系列新的吡咯烷衍生物（化合物5）为有效的ERK1 / 2抑制剂，具有出色的激酶选择性和双重作用机制，但药代动力学（PK）较差。通过发现新的3（S）-硫代甲基吡咯烷类似物7克服了PK的挑战。通过聚焦的结构-活性关系优化前导，导致发现了适用于每日两次口服给药的MK-8353临床候选药物，作为潜在的新型癌症治疗药物。