Discovery of 1,6-naphthyridinone-based MET kinase inhibitor bearing quinoline moiety as promising antitumor drug candidate.,European Journal of Medicinal Chemistry

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Discovery of 1,6-naphthyridinone-based MET kinase inhibitor bearing quinoline moiety as promising antitumor drug candidate.
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-02-21 , DOI: 10.1016/j.ejmech.2020.112174
Tao Chen ₁ , Lin-Sheng Zhuo ₂ , Peng-Fei Liu ₂ , Wei-Rong Fang ₁ , Yun-Man Li ₁ , Wei Huang ₂

Affiliation

A series of 1,6-naphthyridinone-based MET kinase inhibitors bearing quinoline moiety in block A were designed and synthesized based on the structures of Cabozantinib and our reported compound IV. Extensive SAR and DMPK studies led to the identification of 20j, a potent and orally bioavailable MET kinase inhibitor with favorable kinase selectivity. More importantly, 20j exhibited statistically significant tumor growth inhibition (Tumor growth inhibition/TGI of 131%, 4/6 partial regression/PR) in the U-87 MG xeograft model, which is superior to that of Cabozantinib (TGI of 97%, 2/6 PR), and significantly better than that of compound IV (TGI of 15%, 0/6 PR) at the same dose (12.5 mg/kg). Combined with favorable in vitro potency, kinase selectivity, pharmacokinetic profile and in vivo efficacy, the promising antitumor drug candidate 20j has subsequently advanced into preclinical research.

中文翻译：

发现带有喹啉部分的1,6-萘吡啶酮基MET激酶抑制剂是有希望的抗肿瘤药物候选物。

基于卡博替尼和我们报道的化合物Ⅳ的结构，设计和合成了一系列在嵌段A中带有喹啉部分的基于1,6-萘啶酮的MET激酶抑制剂。广泛的SAR和DMPK研究导致了20j的鉴定，20j是一种具有良好激酶选择性的有效且口服可生物利用的MET激酶抑制剂。更重要的是，在U-87 MG异种移植模型中，20j表现出统计学上显着的肿瘤生长抑制作用（肿瘤生长抑制/ TGI为131％，部分消退/ PR为4/6），优于卡波替尼（TGI为97％， 2/6 PR），并且在相同剂量（12.5 mg / kg）时明显优于化合物IV（TGI为15％，0/6 PR）。结合良好的体外效能，激酶选择性，药代动力学特征和体内功效，

更新日期：2020-02-21

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