Discovery of N-(3-((1-Isonicotinoylpiperidin-4-yl)oxy)-4-methylphenyl)-3-(trifluoromethyl)benzamide (CHMFL-KIT-110) as a Selective, Potent, and Orally Available Type II c-KIT Kinase Inhibitor for Gastrointestinal Stromal Tumors (GISTs),Journal of Medicinal Chemistry

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Discovery of N-(3-((1-Isonicotinoylpiperidin-4-yl)oxy)-4-methylphenyl)-3-(trifluoromethyl)benzamide (CHMFL-KIT-110) as a Selective, Potent, and Orally Available Type II c-KIT Kinase Inhibitor for Gastrointestinal Stromal Tumors (GISTs)
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2016-04-14 00:00:00 , DOI: 10.1021/acs.jmedchem.6b00200
Qiang Wang _{1,

2,

3} , Feiyang Liu _{1,

4} , Beilei Wang _{1,

2,

3} , Fengming Zou _{1,

2,

3} , Cheng Chen _{1,

2,

3} , Xiaochuan Liu _{1,

5} , Aoli Wang _{1,

4} , Shuang Qi _{1,

2,

3} , Wenchao Wang _{1,

2,

3} , Ziping Qi _{1,

2,

3} , Zheng Zhao _{1,

2,

3} , Zhenquan Hu _{1,

2,

3} , Wei Wang _{1,

2,

3} , Li Wang _{1,

2,

3} , Shanchun Zhang _{2,

6} , Yuexiang Wang _{7,

8,

9} , Jing Liu _{1,

2,

3} , Qingsong Liu _{1,

2,

3,

4}

Affiliation

High Magnetic Field Laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China
CHMFL-HCMTC Target Therapy Joint Laboratory, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China
Center for Precision Medicine, CAS (Hefei) Institute of Technology Innovation, Hefei Institute of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230088, P. R. China
University of Science and Technology of China, Hefei, Anhui 230036, P. R. China
Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230036, P. R. China
Hefei Cosource Medicine Technology Co., LTD, 358 Ganquan Road, Hefei, Anhui 230031, P. R. China
SIBS (Institute of Health Sciences)-Changzheng Hospital Joint Center for Translational Medicine, Institute of Health Sciences, Shanghai Changzheng Hospital, Institutes for Translational Medicine (CAS-SMMU), Shanghai 200031, China
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, SIBS, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine, Shanghai 200031, China
Collaborative Innovation Center of Systems Biomedicine, Shanghai 200025, China

c-KIT kinase is a validated drug discovery target for gastrointestinal stromal tumors (GISTs). Clinically used c-KIT kinase inhibitors, i.e., Imatinib and Sunitinib, bear other important targets such as ABL or FLT3 kinases. Here we report our discovery of a more selective c-KIT inhibitor, compound 13 (CHMFL-KIT-110), which completely abolished ABL and FLT3 kinase activity. KinomeScan selectivity profiling (468 kinases) of 13 exhibited a high selectivity (S score (1) = 0.01). 13 displayed great antiproliferative efficacy against GISTs cell lines GIST-T1 and GIST-882 (GI₅₀: 0.021 and 0.043 μM, respectively). In the cellular context, it effectively affected c-KIT-mediated signaling pathways and induced apoptosis as well as cell cycle arrest. In addition, 13 possessed acceptable bioavailability (36%) and effectively suppressed the tumor growth in GIST-T1 cell inoculated xenograft model without apparent toxicity. 13 currently is undergoing extensive preclinical evaluation and might be a potential drug candidate for GISTs.

中文翻译：

的发现ñ - （3 - （（1- Isonicotinoylpiperidin -4-基）氧基）-4-甲基苯基）-3-（三氟甲基）苯甲酰胺（CHMFL-KIT-110），为选择性的，有效的，并且可口服类型II C语言-KIT激酶抑制剂在胃肠道间质瘤（GIST）中的应用

c-KIT激酶是胃肠道间质瘤（GIST）的有效药物发现靶标。临床使用的c-KIT激酶抑制剂，即伊马替尼和舒尼替尼，还具有其他重要的靶标，例如ABL或FLT3激酶。在这里，我们报告了我们发现的更具选择性的c-KIT抑制剂化合物13（CHMFL-KIT-110），该化合物完全废除了ABL和FLT3激酶活性。KinomeScan选择性分析（468个激酶）中有13种显示出高选择性（S分数（1）= 0.01）。13展示了对GISTs细胞系GIST-T1和GIST-882（GI ₅₀：分别为0.021和0.043μM）。在细胞环境中，它有效地影响了c-KIT介导的信号通路，并诱导了细胞凋亡以及细胞周期停滞。此外，13个具有可接受的生物利用度（36％），并有效地抑制了GIST-T1细胞接种异种移植模型中的肿瘤生长，而没有明显的毒性。目前有13个正在接受广泛的临床前评估，并且可能是GIST的潜在候选药物。

更新日期：2016-04-14

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