Discovery of 4-methyl-N-(4-((4-methylpiperazin- 1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-oxy)benzamide as a potent inhibitor of RET and its gatekeeper mutant.
Discovery of 4-methyl-N-(4-((4-methylpiperazin- 1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-oxy)benzamide as a potent inhibitor of RET and its gatekeeper mutant.
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4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-((6-(吡啶-3-基)-1H-吡唑并)的发现[
DOI：
10.1016/j.ejmech.2020.112755
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发表时间：
2020-08
影响因子：
6.7
通讯作者：
Xianming Deng
中科院分区：
文献类型：
--
作者：
Xiaoyang Li;Jingyi Su;Yanru Yang;Wenhua Lian;Zhou Deng;Zaiyou Yang;Guyue Chen;Baoding Zhang;Chao Dong;Xueyan Liu;Li Li;Zheng Wang;Zhiyu Hu;Qingyan Xu;Xianming Deng
转染过程中重排的受体酪氨酸激酶 (RET) 在多种癌症中发挥着关键作用，包括甲状腺癌和非小细胞肺癌 (NSCLC)。目前，有几种FDA批准的RET抑制剂，但它们的适应症仅限于甲状腺癌，并且没有一种可以克服它们的看门突变体（V804L和V804M）。在这里，我们报告发现9x代表了一种新化学型的有效和选择性RET抑制剂，使用II型激酶抑制剂的合理设计策略。9x对NSCLC相关的致癌融合KIF5B-RET和CCDC6-RET以及看门人突变转化的Ba/F3细胞表现出优异的抗增殖活性，最低GI50为9 nM，并对野生型RET和RET具有显着的抑制活性突变蛋白，最佳 IC50 为 4 nM。更重要的是，9x还显示出针对 RET 阳性 NSCLC 细胞 LC-2/ad 的纳摩尔效力，但对一组 RET 阴性癌细胞（如 A549、H3122、A375 或亲代 Ba/F3 细胞）没有表现出纳摩尔效力，证明了其选择性“中靶”效应。在小鼠异种移植模型中，9x 以剂量依赖性方式抑制野生型 KIF5B-RET-Ba/F3 和看门突变体 KIF5B-RET(V804M)-Ba/F3 细胞驱动的肿瘤生长。总之，这些数据表明 9x 为开发针对 RET 阳性癌症（尤其是 NSCLC）的靶向疗法提供了良好的起点。
The receptor tyrosine kinase rearranged during transfection (RET) plays pivotal roles in several cancers, including thyroid carcinoma and non-small cell lung cancer (NSCLC). Currently, there are several FDA-approved RET inhibitors, but their indication is limited to thyroid cancer, and none can overcome their gatekeeper mutants (V804L and V804M). Here, we report the discovery of9xrepresenting a new chemotype of potent and selective RET inhibitors, using a rational design strategy of type II kinase inhibitors.9xexhibited both superior antiproliferative activities against NSCLC-related carcinogenic fusions KIF5B-RET and CCDC6-RET and gatekeeper mutant-transformed Ba/F3 cells, with the lowest GI50of 9 nM, and substantial inhibitory activities against wild-type RET and RET mutant proteins, with the best IC50of 4 nM. More importantly,9xalso showed nanomole potency against RET-positive NSCLC cells LC-2/ad, but not against a panel of RET-negative cancer cells, such as A549, H3122, A375 or parental Ba/F3 cells, demonstrating its selective ‘on-target’ effect. In mouse xenograft models,9xrepressed tumor growth driven by both wild type KIF5B-RET-Ba/F3 and gatekeeper mutant KIF5B-RET(V804M)-Ba/F3 cells in a dose-dependent manner. Together, these data establish that9xprovides a good starting point for the development of targeted therapeutics against RET-positive cancers, especially NSCLC.
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影响因子：
7.3
作者：
Vijayan RS;He P;Modi V;Duong-Ly KC;Ma H;Peterson JR;Dunbrack RL Jr;Levy RM
通讯作者：
Levy RM
影响因子：
120.1
作者：
Daniel Jones
通讯作者：
Daniel Jones
影响因子：
82.9
作者：
Kohno T;Ichikawa H;Totoki Y;Yasuda K;Hiramoto M;Nammo T;Sakamoto H;Tsuta K;Furuta K;Shimada Y;Iwakawa R;Ogiwara H;Oike T;Enari M;Schetter AJ;Okayama H;Haugen A;Skaug V;Chiku S;Yamanaka I;Arai Y;Watanabe S;Sekine I;Ogawa S;Harris CC;Tsuda H;Yoshida T;Yokota J;Shibata T
通讯作者：
Shibata T
影响因子：
50.3
作者：
Zou HY;Friboulet L;Kodack DP;Engstrom LD;Li Q;West M;Tang RW;Wang H;Tsaparikos K;Wang J;Timofeevski S;Katayama R;Dinh DM;Lam H;Lam JL;Yamazaki S;Hu W;Patel B;Bezwada D;Frias RL;Lifshits E;Mahmood S;Gainor JF;Affolter T;Lappin PB;Gukasyan H;Lee N;Deng S;Jain RK;Johnson TW;Shaw AT;Fantin VR;Smeal T
通讯作者：
Smeal T
影响因子：
168.9
作者：
Brose, Marcia S.;Nutting, Christopher M.;Jarzab, Barbara;Elisei, Rossella;Siena, Salvatore;Bastholt, Lars;de la Fouchardiere, Christelle;Pacini, Furio;Paschke, Ralf;Shong, Young Kee;Sherman, Steven I.;Smit, Johannes W. A.;Chung, John;Kappeler, Christian;Pena, Carol;Molnar, Istvan;Schlumberger, Martin J.
通讯作者：
Schlumberger, Martin J.