Design and Optimization of 3′-(Imidazo[1,2-a]pyrazin-3-yl)-[1,1′-biphenyl]-3-carboxamides as Selective DDR1 Inhibitors,ACS Medicinal Chemistry Letters

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Design and Optimization of 3′-(Imidazo[1,2-a]pyrazin-3-yl)-[1,1′-biphenyl]-3-carboxamides as Selective DDR1 Inhibitors
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-01-09 , DOI: 10.1021/acsmedchemlett.9b00495
Cheng Mo _{1,

2} , Zhang Zhang ₁ , Yupeng Li _{2,

3} , Minhao Huang ₂ , Jian Zou ₁ , Jinfeng Luo ₂ , Zheng-Chao Tu ₂ , Yong Xu ₂ , Xiaomei Ren ₁ , Ke Ding ₁ , Xiaoyun Lu ₁

Affiliation

DDR1 is considered as a promising target for cancer therapy, and selective inhibitors against DDR1 over other kinases may be considered as promising therapeutic agents. Herein, we have identified a series of 3′-(imidazo[1,2-a]pyrazin-3-yl)-[1,1′-biphenyl]-3-carboxamides as novel selective DDR1 inhibitors. Among these, compound 8v potently inhibited DDR1 with an IC₅₀ of 23.8 nM, while it showed less inhibitory activity against DDR2 (IC₅₀ = 1740 nM) and negligible activities against Bcr-Abl (IC₅₀ > 10 μM) and c-Kit (IC₅₀ > 10 μM). 8v also exhibited excellent selectivity in a KINOMEscan screening platform with 468 kinases. This compound dose-dependently suppressed NSCLC cell tumorigenicity, migration, and invasion. Collectively, these studies support its potential application for treatment of NSCLC.

中文翻译：

3'-（咪唑并[1,2 - a ]吡嗪-3-基）-[1,1'-联苯] -3-羧酰胺作为选择性DDR1抑制剂的设计与优化

DDR1被认为是癌症治疗的有希望的靶标，相对于其他激酶的针对DDR1的选择性抑制剂可能被认为是有希望的治疗剂。在这里，我们已经确定了一系列3'-（咪唑并[1,2 - a ]吡嗪-3-基）-[1,1'-联苯] -3-羧酰胺作为新型选择性DDR1抑制剂。在这些化合物中，化合物8v有效抑制DDR1，IC ₅₀为23.8 nM，而对DDR2的抑制活性较低（IC ₅₀ = 1740 nM），而对Bcr-Abl的抑制活性却很小，IC ₅₀ > 10μM IC ₅₀ > 10μM）。8伏在具有468种激酶的KINOMEscan筛选平台中，也显示出优异的选择性。该化合物剂量依赖性地抑制了NSCLC细胞的致瘤性，迁移和侵袭。这些研究共同支持其在治疗非小细胞肺癌中的潜在应用。

更新日期：2020-01-10

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