2. Academic Validation
  3. Identification of a potent 5-phenyl-thiazol-2-ylamine-based inhibitor of FLT3 with activity against drug resistance-conferring point mutations

Identification of a potent 5-phenyl-thiazol-2-ylamine-based inhibitor of FLT3 with activity against drug resistance-conferring point mutations

  • Eur J Med Chem. 2015 Jul 15:100:151-61. doi: 10.1016/j.ejmech.2015.05.008.
Chiung-Tong Chen 1,  John T-A Hsu 1,  Wen-Hsing Lin 1,  Cheng-Tai Lu 1,  Shih-Chieh Yen 1,  Tsu Hsu 1,  Yu-Ling Huang 1,  Jen-Shin Song 1,  Chun-Hwa Chen 1,  Ling-Hui Chou 1,  Kuei-Jung Yen 1,  Ching-Ping Chen 1,  Po-Chu Kuo 1,  Chen-Lung Huang 1,  H Eugene Liu 2,  Yu-Sheng Chao 1,  Teng-Kuang Yeh 1,  Weir-Torn Jiaang 3
Affiliations

Affiliations

  • 1 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Rd., Zhunan Town, Miaoli County 350, Taiwan, ROC.
  • 2 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.
  • 3 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.
PMID: 26081023 DOI: 10.1016/j.ejmech.2015.05.008
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.

Keywords

Acute myeloid leukemia; FLT3 inhibitor; ITD/D835Y; Receptor tyrosine kinase; Xenograft model.

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