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)

Qiang Wang; Feiyang Liu; Beilei Wang; Fengming Zou; Cheng Chen; Xiaochuan Liu; Aoli Wang; Shuang Qi; Wenchao Wang; Ziping Qi; Zheng Zhao; Zhenquan Hu; Wei Wang; Li Wang; Shanchun Zhang; Yuexiang Wang; Jing Liu; Qingsong Liu

doi:10.1021/acs.jmedchem.6b00200

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)

J Med Chem. 2016 Apr 28;59(8):3964-79. doi: 10.1021/acs.jmedchem.6b00200. Epub 2016 Apr 14.

Authors

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}

Affiliations

¹ High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.
² CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.
³ 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.
⁴ University of Science and Technology of China , Hefei, Anhui 230036, P. R. China.
⁵ Department of Chemistry, University of Science and Technology of China , Hefei, Anhui 230036, P. R. China.
⁶ Hefei Cosource Medicine Technology Co., LTD , 358 Ganquan Road, Hefei, Anhui 230031, P. R. China.
⁷ 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.
⁸ 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.
⁹ Collaborative Innovation Center of Systems Biomedicine , Shanghai 200025, China.

PMID: 27077705
DOI: 10.1021/acs.jmedchem.6b00200

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Animals
Area Under Curve
Benzamides / administration & dosage
Benzamides / chemistry*
Benzamides / pharmacology*
Benzamides / therapeutic use
Cell Line, Tumor
Drug Discovery
Gastrointestinal Stromal Tumors / drug therapy*
Gastrointestinal Stromal Tumors / enzymology
Half-Life
Humans
Isonicotinic Acids / administration & dosage
Isonicotinic Acids / chemistry*
Isonicotinic Acids / pharmacology*
Isonicotinic Acids / therapeutic use
Mice
Protein Kinase Inhibitors / administration & dosage
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology*
Protein Kinase Inhibitors / therapeutic use
Rats
Structure-Activity Relationship

Substances

Benzamides
CHMFL-KIT-110
Isonicotinic Acids
Protein Kinase Inhibitors