Discovery of 2-(4-chloro-3-(trifluoromethyl)phenyl)-N-(4-((6,7-dimethoxyquinolin-4-yl )oxy)phenyl)acetamide (CHMFL-KIT-64) as a Novel Orally Available Potent Inhibitor against Broad Spectrum Mutants of c-KIT Kinase for Gastrointestinal Stromal Tumors
Discovery of 2-(4-chloro-3-(trifluoromethyl)phenyl)-N-(4-((6,7-dimethoxyquinolin-4-yl )oxy)phenyl)acetamide (CHMFL-KIT-64) as a Novel Orally Available Potent Inhibitor against Broad Spectrum Mutants of c-KIT Kinase for Gastrointestinal Stromal Tumors
复制标题
发现2-(4-氯-3-(三氟甲基)苯基)-N-(4-((6,7-二甲氧基喹啉-4-基)氧基)苯基)乙酰胺(CHMFL-KIT-64)作为一种新型口服药物
DOI：
10.1021/acs.jmedchem.9b00280
复制
发表时间：
2019
影响因子：
7.3
通讯作者：
Liu Jing
中科院分区：
文献类型：
--
作者：
Wu Yun;Wang Beilei;Wang Junjie;Qi Shuang;Zou Fengming;Qi Ziping;Liu Feiyang;Liu Qingwang;Chen Cheng;Hu Chen;Hu Zhenquan;Wang Aoli;Wang Li;Wang Wenchao;Ren Tao;Cai Yujiao;Bai Mingfeng;Liu Qingsong;Liu Jing
从我们先前开发的c-KIT激酶抑制剂CHMFL-KIT-8140开始，通过II型激酶抑制剂结合元件杂交设计方法，我们发现了一种新的c-KIT激酶抑制剂化合物18（CHMFL-KIT-64），其对c-KIT wt和广谱耐药突变体有效，具有改善的生物利用度。18对c-KIT激酶和c-KIT T670 I在生化试验中突变，并对质膜结构域中的大多数功能获得性突变、ATP结合口袋（V654 A除外）和激活环（D816 V除外）中的耐药突变显示出很强的效力。此外，18在不同种属（包括小鼠、大鼠和犬）中表现出良好的体内药代动力学（PK）特征。在c-KIT T670 I、D820 G和Y823 D muplatin介导的小鼠模型以及已知对伊马替尼耐药的c-KIT wt患者原代细胞中，也显示出良好的体内抗肿瘤疗效。对广谱临床重要的c-KIT突变体的有效活性结合良好的体内PK/药效学特性18表明它可能是胃肠道间质瘤的新的潜在治疗候选药物。
Starting from our previously developed c-KIT kinase inhibitor CHMFL-KIT-8140, through a type II kinase inhibitor binding element hybrid design approach, we discovered a novel c-KIT kinase inhibitor compound18(CHMFL-KIT-64), which is potent against c-KIT wt and a broad spectrum of drug-resistant mutants with improved bioavailability.18exhibits single-digit nM potency against c-KIT kinase and c-KIT T670I mutants in the biochemical assay and displays great potencies against most of the gain-of-function mutations in the juxtamembrane domain, drug-resistant mutations in the ATP binding pocket (except V654A), and activation loops (except D816V). In addition,18exhibits a good in vivo pharmacokinetic (PK) profile in different species including mice, rats, and dogs. It also displays good in vivo antitumor efficacy in the c-KIT T670I, D820G, and Y823D mutant-mediated mice models as well as in the c-KIT wt patient primary cells which are known to be imatinib-resistant. The potent activity against a broad spectrum of clinically important c-KIT mutants combining the good in vivo PK/pharmacodynamic properties of18indicates that it might be a new potential therapeutic candidate for gastrointestinal stromal tumors.