title: Identification of a potent 5-phenyl-thiazol-2-ylamine-based inhibitor of FLT3 with activity against drug resistance-conferring point mutations.
abstract: Numerous FLT3 inhibitors have been explored as a viable therapy for the treatment of acute myeloid leukemia (AML). However, clinical data have been underwhelming due to incomplete inhibition of FLT3 or the emergence of resistant mutations treated with these older agents. We previously developed a series of 3-phenyl-1H-5-pyrazolylamine derivatives as highly potent and selective FLT3 inhibitors with good in vivo efficacy using an intravenous (IV) route. However, the poor bioavailability of these pyrazole compounds limits the development of these promising antileukemic compounds for clinical use. Herein, we describe a novel class of 5-phenyl-thiazol-2-ylamine compounds that are multi-targeted FLT3 inhibitors. From this class of compounds, compound 7h was very potent against AML cell lines and exhibited excellent oral efficacy in AML xenograft models. In addition, further studies demonstrated that compound 7h exhibited potent in vitro and in vivo activities against clinically relevant AC220 (3)-resistant kinase domain mutants of FLT3-ITD.
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Rd., Zhunan Town, Miaoli County 350, Taiwan, ROC.
authors.forename: Chiung-Tong
authors.initials: CT
authors.lastname: Chen
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Rd., Zhunan Town, Miaoli County 350, Taiwan, ROC.
authors.forename: John T-A
authors.initials: JT
authors.lastname: Hsu
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Rd., Zhunan Town, Miaoli County 350, Taiwan, ROC.
authors.forename: Wen-Hsing
authors.initials: WH
authors.lastname: Lin
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Rd., Zhunan Town, Miaoli County 350, Taiwan, ROC.
authors.forename: Cheng-Tai
authors.initials: CT
authors.lastname: Lu
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Rd., Zhunan Town, Miaoli County 350, Taiwan, ROC.
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Yen
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Rd., Zhunan Town, Miaoli County 350, Taiwan, ROC.
authors.forename: Tsu
authors.initials: T
authors.lastname: Hsu
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Rd., Zhunan Town, Miaoli County 350, Taiwan, ROC.
authors.forename: Yu-Ling
authors.initials: YL
authors.lastname: Huang
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Rd., Zhunan Town, Miaoli County 350, Taiwan, ROC.
authors.forename: Jen-Shin
authors.initials: JS
authors.lastname: Song
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Rd., Zhunan Town, Miaoli County 350, Taiwan, ROC.
authors.forename: Chun-Hwa
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Rd., Zhunan Town, Miaoli County 350, Taiwan, ROC.
authors.forename: Ling-Hui
authors.initials: LH
authors.lastname: Chou
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Rd., Zhunan Town, Miaoli County 350, Taiwan, ROC.
authors.forename: Kuei-Jung
authors.initials: KJ
authors.lastname: Yen
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Rd., Zhunan Town, Miaoli County 350, Taiwan, ROC.
authors.forename: Ching-Ping
authors.initials: CP
authors.lastname: Chen
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Rd., Zhunan Town, Miaoli County 350, Taiwan, ROC.
authors.forename: Po-Chu
authors.initials: PC
authors.lastname: Kuo
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Rd., Zhunan Town, Miaoli County 350, Taiwan, ROC.
authors.forename: Chen-Lung
authors.initials: CL
authors.lastname: Huang
authors.affiliation: Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan, ROC; Division of Hematology and Oncology, Department of Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan, ROC.
authors.forename: H Eugene
authors.initials: HE
authors.lastname: Liu
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Rd., Zhunan Town, Miaoli County 350, Taiwan, ROC.
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Chao
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Rd., Zhunan Town, Miaoli County 350, Taiwan, ROC.
authors.forename: Teng-Kuang
authors.initials: TK
authors.lastname: Yeh
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Rd., Zhunan Town, Miaoli County 350, Taiwan, ROC. Electronic address: wtjiaang@nhri.org.tw.
authors.forename: Weir-Torn
authors.initials: WT
authors.lastname: Jiaang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D017354:Point Mutation / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: C000607119:5-phenyl-thiazol-2-ylamine; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D013844:Thiazoles; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3
keywords: Acute myeloid leukemia; FLT3 inhibitor; ITD/D835Y; Receptor tyrosine kinase; Xenograft model