2. Academic Validation
  3. Discovery and evaluation of 3-phenyl-1H-5-pyrazolylamine-based derivatives as potent, selective and efficacious inhibitors of FMS-like tyrosine kinase-3 (FLT3)

Discovery and evaluation of 3-phenyl-1H-5-pyrazolylamine-based derivatives as potent, selective and efficacious inhibitors of FMS-like tyrosine kinase-3 (FLT3)

  • Bioorg Med Chem. 2011 Jul 15;19(14):4173-82. doi: 10.1016/j.bmc.2011.06.016.
Wen-Hsing Lin 1,  Shu-Yi Hsieh,  Shih-Chieh Yen,  Chiung-Tong Chen,  Teng-Kuang Yeh,  Tsu Hsu,  Cheng-Tai Lu,  Ching-Ping Chen,  Chun-Wha Chen,  Ling-Hui Chou,  Yu-Lin Huang,  An-Huei Cheng,  Yun-I Chang,  Ya-Ju Tseng,  Kuei-Rong Yen,  Yu-Sheng Chao,  John T-A Hsu,  Weir-Torn Jiaang
Affiliations

Affiliation

  • 1 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Rd., Zhunan Town, Miaoli Country 350, Taiwan, ROC.
PMID: 21708468 DOI: 10.1016/j.bmc.2011.06.016
Abstract

Preclinical investigations and early clinical trial studies suggest that FLT3 inhibitors offer a viable therapy for acute myeloid leukemia. However, early clinical data for direct FLT3 inhibitors provided only modest results because of the failure to fully inhibit FLT3. We have designed and synthesized a novel class of 3-phenyl-1H-5-pyrazolylamine-derived compounds as FLT3 inhibitors which exhibit potent FLT3 inhibition and high selectivity toward different Receptor Tyrosine Kinases. The structure-activity relationships led to the discovery of two series of FLT3 inhibitors, and some potent compounds within these two series exhibited comparable potency to FLT3 inhibitors sorafenib (3) and ABT-869 (4) in both wt-FLT3 Enzyme inhibition and FLT3-ITD inhibition on cell growth (MOLM-13 and MV4;11 cells). In particular, the selected compound 12a exhibited the ability to regress tumors in mouse xenograft models using MOLM-13 and MV4;11 cells.

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