An orally available tyrosine kinase ALK and RET dual inhibitor bearing the tetracyclic benzo[b]carbazolone core
An orally available tyrosine kinase ALK and RET dual inhibitor bearing the tetracyclic benzo[b]carbazolone core
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一种口服酪氨酸激酶 ALK 和 RET 双重抑制剂，具有四环苯并[b]咔唑酮核心
DOI：
10.1016/j.ejmech.2016.04.046
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发表时间：
2016
影响因子：
6.7
通讯作者：
Zhang Ao
中科院分区：
文献类型：
--
作者：
Song Zilan;Xia Zongjun;Ji Yinchun;Xing Li;Gao Yinglei;Ai Jing;Geng Meiyu;Zhang Ao
我们的早期构效关系研究已确定苯并[b]咔唑酮 6 是一种高效口服生物可利用的 ALK 抑制剂。进一步的先导分析表明，6 对 ALK 抗性和热点激活突变体均具有活性，并且对 RET 激酶也具有高效作用。在 NIH/3T3-EML4-ALK 和 NIH/3T3-EML4-ALK L1196M 异种移植模型中均实现了肿瘤停滞和部分肿瘤消退。基于最佳的体外和体内抗肿瘤功效，compound6 现在正在我们的临床前环境中作为一种新的口服 ALK/RET 双抑制剂进行进一步分析。
Our early structure–activity relationship study has identified benzo[b]carbazolone6as a high potency orally bioavailable ALK inhibitor. Further lead profiling disclosed that6is active against both ALK resistant and hot spot-activating mutants, and is also highly potent against RET kinase. Tumor stasis and partial tumor regression were achieved with6in both NIH/3T3-EML4-ALK and NIH/3T3-EML4-ALK L1196M xenograft models. Based on the optimal in vitro and in vivo antitumor efficacy, compound6is now being profiled further in our preclinical settings as a new orally available ALK/RET dual inhibitor.