Synthesis and biological evaluation of diaryl urea derivatives as FLT3 inhibitors

  • Bioorg Med Chem Lett. 2020 Dec 1;30(23):127525. doi: 10.1016/j.bmcl.2020.127525.
Qing Zhang  1 ,  Kuantao Zhao  1 ,  Lixun Zhang  1 ,  Xiaoyu Jiao  1 ,  Yongjie Zhang  1 ,  Chunlei Tang  2
Affiliations
  • 1. School of Pharmaceutical Science, Jiangnan University, Wuxi, China.
  • 2. School of Pharmaceutical Science, Jiangnan University, Wuxi, China. Electronic address: [email protected].
PMID: 32898697 DOI: 10.1016/j.bmcl.2020.127525
Abstract

As a class III receptor tyrosine kinase (RTK), FMS-like tyrosine kinase 3 (FLT3) is always overexpressed in many cases of acute leukemia. This paper studies the structure-based synthesis and biological evaluation of diaryl urea derivatives as FLT3 inhibitors. Encouragingly, compounds 15b, 16b, 24a, and 24c showed excellent biological activities in a low nanomolar range. In particular, compound 16b demonstrated significant inhibitory potency against FLT3-ITD (IC50 = 5.60 nM) and better antiproliferative activity than quizartinib against MV4-11 cell line (IC50 = 0.176 nM). It is indicated that compound 16b for the treatment of acute myeloid leukemia could be very promising.

Keywords
Biological evaluation; FLT3 inhibitor; Internal tandem duplication; MV4-11.