title: Novel thiazole amine class tyrosine kinase inhibitors induce apoptosis in human mast cells expressing D816V KIT mutation.
abstract: Gain-of-function mutations of receptor tyrosine kinase KIT play a critical role in the pathogenesis of systemic mastocytosis (SM) and gastrointestinal stromal tumors. D816V KIT mutation, found in ∼80% of SM, is resistant to the currently available tyrosine kinase inhibitors (TKIs) (e.g. imatinib mesylate). Therefore, development of promising TKIs for the treatment of D816V KIT mutation is still urgently needed. We synthesized thiazole amine compounds and chose one representative designated 126332 to investigate its effect on human mast cells expressing KIT mutations. We found 126332 inhibited the phosphorylation of KIT and its downstream signaling molecules Stat3 and Stat5. 126332 inhibited the proliferation of D816V KIT expressing cells. 126332 induced apoptosis and downregulated levels of Mcl-1 and survivin. Furthermore, 126332 inhibited the tyrosine phosphorylation of β-catenin, inhibited β-catenin-mediated transcription and DNA binding of TCF. Moreover, 126332 also exhibited in vivo antineoplastic activity against cells harboring D816V mutation. Our findings suggest thiazole amine compounds may be promising agents for the treatment of diseases caused by KIT mutation.
authors.affiliation: Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Key Laboratory of Regenerative Biology and Institute of Chemical Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Ding
authors.affiliation: Key Laboratory of Regenerative Biology and Institute of Chemical Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Deping
authors.initials: D
authors.lastname: Wang
authors.affiliation: Key Laboratory of Regenerative Biology and Institute of Chemical Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Mengjie
authors.initials: M
authors.lastname: Shen
authors.affiliation: Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China. Electronic address: panjx2@mail.sysu.edu.cn.
authors.forename: Jingxuan
authors.initials: J
authors.lastname: Pan
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005838:Genotype; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000637:transplantation; D034801:Mastocytoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009154:Mutation; D010641:Phenotype; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D000588:Amines; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D013844:Thiazoles; D019009:Proto-Oncogene Proteins c-kit
keywords: D816V mutation; Imatinib-resistance; KIT; Tyrosine kinase inhibitor