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

Chiung Tong Chen, John T A Hsu, Wen Hsing Lin, Cheng Tai Lu, Shih Chieh Yen, Tsu Hsu, Yu Ling Huang, Jen Shin Song, Chun Hwa Chen, Ling Hui Chou, Kuei Jung Yen, Ching Ping Chen, Po Chu Kuo, Chen Lung Huang, H. Eugene Liu, Yu Sheng Chao, Teng Kuang Yeh, Weir Torn Jiaang

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number7887
Pages (from-to)151-161
Number of pages11
JournalEuropean Journal of Medicinal Chemistry
Volume100
DOIs
Publication statusPublished - Jun 14 2015

Fingerprint

Point Mutation
Drug Resistance
Heterografts
Acute Myeloid Leukemia
Phosphotransferases
Cells
Derivatives
Pharmaceutical Preparations
Myeloid Cells
Biological Availability
Cell Line
Mutation
5-phenyl-thiazol-2-ylamine
pyrazole
Therapeutics

Keywords

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

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology
  • Medicine(all)

Cite this

Identification of a potent 5-phenyl-thiazol-2-ylamine-based inhibitor of FLT3 with activity against drug resistance-conferring point mutations. / Chen, Chiung Tong; Hsu, John T A; Lin, Wen Hsing; Lu, Cheng Tai; Yen, Shih Chieh; Hsu, Tsu; Huang, Yu Ling; Song, Jen Shin; Chen, Chun Hwa; Chou, Ling Hui; Yen, Kuei Jung; Chen, Ching Ping; Kuo, Po Chu; Huang, Chen Lung; Liu, H. Eugene; Chao, Yu Sheng; Yeh, Teng Kuang; Jiaang, Weir Torn.

In: European Journal of Medicinal Chemistry, Vol. 100, 7887, 14.06.2015, p. 151-161.

Research output: Contribution to journalArticle

Chen, CT, Hsu, JTA, Lin, WH, Lu, CT, Yen, SC, Hsu, T, Huang, YL, Song, JS, Chen, CH, Chou, LH, Yen, KJ, Chen, CP, Kuo, PC, Huang, CL, Liu, HE, Chao, YS, Yeh, TK & Jiaang, WT 2015, 'Identification of a potent 5-phenyl-thiazol-2-ylamine-based inhibitor of FLT3 with activity against drug resistance-conferring point mutations', European Journal of Medicinal Chemistry, vol. 100, 7887, pp. 151-161. https://doi.org/10.1016/j.ejmech.2015.05.008
Chen, Chiung Tong ; Hsu, John T A ; Lin, Wen Hsing ; Lu, Cheng Tai ; Yen, Shih Chieh ; Hsu, Tsu ; Huang, Yu Ling ; Song, Jen Shin ; Chen, Chun Hwa ; Chou, Ling Hui ; Yen, Kuei Jung ; Chen, Ching Ping ; Kuo, Po Chu ; Huang, Chen Lung ; Liu, H. Eugene ; Chao, Yu Sheng ; Yeh, Teng Kuang ; Jiaang, Weir Torn. / Identification of a potent 5-phenyl-thiazol-2-ylamine-based inhibitor of FLT3 with activity against drug resistance-conferring point mutations. In: European Journal of Medicinal Chemistry. 2015 ; Vol. 100. pp. 151-161.
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abstract = "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.",
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AU - Lu, Cheng Tai

AU - Yen, Shih Chieh

AU - Hsu, Tsu

AU - Huang, Yu Ling

AU - Song, Jen Shin

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AU - Chen, Ching Ping

AU - Kuo, Po Chu

AU - Huang, Chen Lung

AU - Liu, H. Eugene

AU - Chao, Yu Sheng

AU - Yeh, Teng Kuang

AU - Jiaang, Weir Torn

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N2 - 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.

AB - 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.

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