A series of novel 4-chloro-benzamides derivatives containing substituted five-membered heteroaryl ring were designed, synthesized and evaluated as RET kinase inhibitors for cancer therapy. Most of compounds exhibited moderate to high potency in ELISA-based kinase assay. In particular, compound I-8 containing 1,2,4-oxadiazole strongly inhibited RET kinase activity both in molecular and cellular level. In turn, I-8 inhibited cell proliferation driven by RET wildtype and gatekeeper mutation. The results implied that 4-chloro-3-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl)benzamides are promising lead compounds as novel RET kinase inhibitor for further investigation.

中文翻译：

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发现4-氯-3-（5-（吡啶-3-基）-1,2,4-恶二唑-3-基）苯甲酰胺为新型RET激酶抑制剂

设计，合成和评估了一系列含有取代的五元杂芳基环的新型4-氯苯甲酰胺衍生物，并将其作为用于癌症治疗的RET激酶抑制剂进行了评估。大多数化合物在基于ELISA的激酶测定中表现出中等至高的效力。特别地，包含1,2,4-恶二唑的化合物I-8在分子和细胞水平上都强烈抑制RET激酶活性。反过来，I-8抑制了RET野生型和关守突变驱动的细胞增殖。结果表明4-氯-3-（5-（吡啶-3-基）-1，2，4-恶二唑-3-基）苯甲酰胺是有前途的铅化合物，可作为进一步研究的新型RET激酶抑制剂。