title: Discovery of N-((1-(4-(3-(3-((6,7-Dimethoxyquinolin-3-yl)oxy)phenyl)ureido)-2-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)propionamide (CHMFL-KIT-8140) as a Highly Potent Type II Inhibitor Capable of Inhibiting the T670I "Gatekeeper" Mutant of cKIT Kinase.
abstract: cKIT kinase inhibitors, e.g., imatinib, could induce drug-acquired mutations such as cKIT T670I that rendered drug resistance after chronic treatment. Through a type II kinase inhibitor design approach we discovered a highly potent type II cKIT kinase inhibitor compound 35 (CHMFL-KIT-8140), which potently inhibited both cKIT wt (IC50 = 33 nM) and cKIT gatekeeper T670I mutant (IC50 = 99 nM). Compound 35 displayed strong antiproliferative effect against GISTs cancer cell lines GIST-T1 (cKIT wt, GI50 = 4 nM) and GIST-5R (cKIT T670I, GI50 = 26 nM). In the cellular context it strongly inhibited c-KIT mediated signaling pathways and induced apoptosis. In the BaF3-TEL-cKIT-T670I isogenic cell inoculated xenograft mouse model, 35 exhibited dose dependent tumor growth suppression efficacy and 100 mg/kg dosage provided 47.7% tumor growth inhibition (TGI) without obvious toxicity. We believe compound 35 would be a good pharmacological tool for exploration of the cKIT-T670I mutant mediated pathology in GISTs.
authors.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.
authors.forename: Binhua
authors.initials: B
authors.lastname: Li
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|University of Science and Technology of China , Hefei, Anhui 230036, P. R. China.
authors.forename: Aoli
authors.initials: A
authors.lastname: Wang
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.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.
authors.forename: Ziping
authors.initials: Z
authors.lastname: Qi
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.
authors.forename: Xiaochuan
authors.initials: X
authors.lastname: Liu
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|University of Science and Technology of China , Hefei, Anhui 230036, P. R. China.
authors.forename: Kailin
authors.initials: K
authors.lastname: Yu
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.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.
authors.forename: Cheng
authors.initials: C
authors.lastname: Chen
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|University of Science and Technology of China , Hefei, Anhui 230036, P. R. China.
authors.forename: Chen
authors.initials: C
authors.lastname: Hu
authors.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.
authors.forename: Wenchao
authors.initials: W
authors.lastname: Wang
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|University of Science and Technology of China , Hefei, Anhui 230036, P. R. China.
authors.forename: Jiaxin
authors.initials: J
authors.lastname: Wu
authors.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.
authors.forename: Zhenquan
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences , Hefei, Anhui 230088, P. R. China.
authors.forename: Ling
authors.initials: L
authors.lastname: Ye
authors.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.
authors.forename: Fengming
authors.initials: F
authors.lastname: Zou
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|University of Science and Technology of China , Hefei, Anhui 230036, P. R. China.
authors.forename: Feiyang
authors.initials: F
authors.lastname: Liu
authors.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.
authors.forename: Beilei
authors.initials: B
authors.lastname: Wang
authors.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.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences , Hefei, Anhui 230088, P. R. China.
authors.forename: Tao
authors.initials: T
authors.lastname: Ren
authors.affiliation: Molecular Imaging Laboratory, Department of Radiology, University of Pittsburgh , Pittsburgh, Pennsylvania 15219, United States.|Department of Bioengineering, University of Pittsburgh , Pittsburgh, Pennsylvania 15261, United States.|University of Pittsburgh Cancer Institute , Pittsburgh, Pennsylvania 15232, United States.
authors.forename: Shaojuan
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Molecular Imaging Laboratory, Department of Radiology, University of Pittsburgh , Pittsburgh, Pennsylvania 15219, United States.|Department of Bioengineering, University of Pittsburgh , Pittsburgh, Pennsylvania 15261, United States.|University of Pittsburgh Cancer Institute , Pittsburgh, Pennsylvania 15232, United States.
authors.forename: Mingfeng
authors.initials: M
authors.lastname: Bai
authors.affiliation: CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|Hefei Cosource Medicine Technology Co. LTD. , 358 Ganquan Road, Hefei, Anhui 230031, P. R. China.
authors.forename: Shanchun
authors.initials: S
authors.lastname: Zhang
authors.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.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.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.|University of Science and Technology of China , Hefei, Anhui 230036, P. R. China.|Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences , Hefei, Anhui 230088, P. R. China.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Liu
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D054879:Halogenation; D006801:Humans; D008745:Methylation; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D047428:Protein Kinase Inhibitors; D019009:Proto-Oncogene Proteins c-kit; C034666:propionamide