MK-8353: Discovery of an Orally Bioavailable Dual Mechanism ERK Inhibitor for Oncology
MK-8353: Discovery of an Orally Bioavailable Dual Mechanism ERK Inhibitor for Oncology
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DOI：
10.1021/acsmedchemlett.8b00220
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发表时间：
2018-07-01
影响因子：
4.2
通讯作者：
Samatar, Ahmed A.
中科院分区：
文献类型：
--
作者：
Boga, Sobhana Babu;Deng, Yongqi;Samatar, Ahmed A.
新的免疫癌症疗法的出现和发展引发了人们对发现治疗癌症的新途径的兴趣迅速增长。为此，一系列新的吡咯烷衍生物（化合物5）被鉴定为ERK 1/2的有效抑制剂，具有优异的激酶选择性和双重作用机制，但具有差的药代动力学（PK）。PK的挑战通过发现新的3（S）-硫代甲基吡咯烷类似物7而克服。通过聚焦结构-活性关系进行的先导物优化导致发现了一种临床候选药物MK-8353，适合作为潜在的新型癌症治疗药物每日两次口服给药。
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.