Development of a potent and selective FLT3 kinase inhibitor by systematic expansion of a non-selective fragment-screening hit

Hirofumi Nakano; Tsukasa Hasegawa; Riyo Imamura; Nae Saito; Hirotatsu Kojima; Takayoshi Okabe; Tetsuo Nagano

doi:10.1016/j.bmcl.2016.03.006

Development of a potent and selective FLT3 kinase inhibitor by systematic expansion of a non-selective fragment-screening hit

Bioorg Med Chem Lett. 2016 May 1;26(9):2370-4. doi: 10.1016/j.bmcl.2016.03.006. Epub 2016 Mar 3.

Authors

Hirofumi Nakano¹, Tsukasa Hasegawa¹, Riyo Imamura¹, Nae Saito¹, Hirotatsu Kojima¹, Takayoshi Okabe¹, Tetsuo Nagano²

Affiliations

¹ Drug Discovery Initiative, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
² Drug Discovery Initiative, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan. Electronic address: tlong@mol.f.u-tokyo.ac.jp.

PMID: 26995531
DOI: 10.1016/j.bmcl.2016.03.006

Abstract

A non-selective inhibitor (1) of FMS-like tyrosine kinase-3 (FLT3) was identified by fragment screening and systematically modified to afford a potent and selective inhibitor 26. We confirmed that 26 inhibited the growth of FLT-3-activated human acute myeloid leukemia cell line MV4-11. Our design strategy enabled rapid development of a novel type of FLT3 inhibitor from the hit fragment in the absence of target-structural information.

Keywords: Acute myeloid leukemia; FLT3; Fragment based drug discovery; Kinase inhibitor; Kinase selectivity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Humans
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship
fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*

Substances

Protein Kinase Inhibitors
FLT3 protein, human
fms-Like Tyrosine Kinase 3