- Identification of a Multitargeted Tyrosine Kinase Inhibitor for the Treatment of Gastrointestinal Stromal Tumors and Acute Myeloid Leukemia
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Gastrointestinal stromal tumors (GISTs) are prototypes of stem cell factor receptor (c-KIT)-driven cancer. Two receptor tyrosine kinases, c-KIT and fms-tyrosine kinase (FLT3), are frequently mutated in acute myeloid leukemia (AML) patients, and these mutations are associated with poor prognosis. In this study, we discovered a multitargeted tyrosine kinase inhibitor, compound 15a, with potent inhibition against single or double mutations of c-KIT developed in GISTs. Moreover, crystal structure analysis revealed the unique binding mode of 15a with c-KIT and may elucidate its high potency in inhibiting c-KIT kinase activity. Compound 15a inhibited cell proliferation and induced apoptosis by targeting c-KIT in c-KIT-mutant GIST cell lines. The antitumor effects of 15a were also demonstrated in GIST430 and GIST patient-derived xenograft models. Further studies demonstrated that 15a inhibited the proliferation of c-KIT- and FLT3-driven AML cells in vitro and in vivo. The results of this study suggest that 15a may be a potential anticancer drug for the treatment of GISTs and AML.
- Lin, Wen-Hsing,Wu, Su-Ying,Yeh, Teng-Kuang,Chen, Chiung-Tong,Song, Jen-Shin,Shiao, Hui-Yi,Kuo, Ching-Chuan,Hsu, Tsu,Lu, Cheng-Tai,Wang, Pei-Chen,Wu, Tsung-Sheng,Peng, Yi-Hui,Lin, Hui-You,Chen, Ching-Ping,Weng, Ya-Ling,Kung, Fang-Chun,Wu, Mine-Hsine,Su, Yu-Chieh,Huang, Kuo-Wei,Chou, Ling-Hui,Hsueh, Ching-Cheng,Yen, Kuei-Jung,Kuo, Po-Chu,Huang, Chen-Lung,Chen, Li-Tzong,Shih, Chuan,Tsai, Hui-Jen,Jiaang, Weir-Torn
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p. 11135 - 11150
(2019/12/30)
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- AMINOTHIAZOLE COMPOUNDS AS PROTEIN KINASE INHIBITORS
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Aminothiazole compounds of Formula (I) shown below and pharmaceutical compositions containing one of such compounds: Also disclosed are methods of inhibiting a tyrosine kinase and treating cancer associated with a tyrosine kinase with one of the aminothiazole compounds.
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Paragraph 0052-0055
(2019/01/04)
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- SULFONYLAMINOPYRIDINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
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Provided are sulfonylaminopyridine compounds that are inhibitors of ITK kinase, compositions containing these compounds and methods for treating diseases mediated by ITK kinase. In particular, provided are compounds of Formula (I), (II) or (III), stereoisomers, tautomers, solvates, prodrugs or pharmaceutically acceptable salts thereof, where n, R1, R2, R3, R6 and R7 are defined herein, pharmaceutical compositions comprising the compound and a pharmaceutically acceptable carrier, adjuvant or vehicle, methods of using the compound or composition in therapy, for example, for treating a disease or condition mediated by ITK kinase in a patient.
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Page/Page column 122
(2016/01/25)
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- Aminopyrazole-phenylalanine based GPR142 agonists: Discovery of tool compound and in vivo efficacy studies
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Herein, we report the lead optimization of amrinone-phenylalanine based GPR142 agonists. Structure-activity relationship studies led to the discovery of aminopyrazole-phenylalanine carboxylic acid 22, which exhibited good agonistic activity, high target selectivity, desirable pharmacokinetic properties, and no cytochrome P450 or hERG liability. Compound 22, together with its orally bioavailable ethyl ester prodrug 23, were found to be suitable for in vivo proof-of-concept studies. Compound 23 displayed good efficacy in a mouse oral glucose tolerance test (OGTT). Compound 22 showed GPR142 dependent stimulation of insulin secretion in isolated mouse islets and demonstrated a statistically significant glucose lowering effect in a mouse model bearing transplanted human islets.
- Yu, Ming,Lizarzaburu, Mike,Motani, Alykhan,Fu, Zice,Du, Xiaohui,Liu, Jiwen,Jiao, Xianyun,Lai, Sujen,Fan, Peter,Fu, Angela,Liu, Qingxiang,Murakoshi, Michiko,Nara, Futoshi,Oda, Kozo,Okuyama, Ryo,Reagan, Jeff D.,Watanabe, Nobuaki,Yamazaki, Mami,Xiong, Yumei,Zhang, Ying,Zhuang, Run,Lin, Daniel C.-H.,Houze, Jonathan B.,Medina, Julio C.,Li, Leping
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supporting information
p. 829 - 834
(2013/10/01)
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- PHENYLALANINE AMIDE DERIVATIVES USEFUL FOR TREATING INSULIN-RELATED DISEASES AND CONDITIONS
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Provided herein are compounds of formula I: wherein A, B, X, R1 , R2 and subscript n are as defined in the following disclosure. Compositions comprising the compounds are also provided, as well as methods for their use, for example, in treatment of type 2 diabetes and type 2 diabetes-related conditions
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Page/Page column 43
(2010/09/03)
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