UNC2025, a potent and orally bioavailable MER/FLT3 dual inhibitor.

Abstract:

:We previously reported a potent small molecule Mer tyrosine kinase inhibitor UNC1062. However, its poor PK properties prevented further assessment in vivo. We report here the sequential modification of UNC1062 to address DMPK properties and yield a new potent and highly orally bioavailable Mer inhibitor, 11, capable of inhibiting Mer phosphorylation in vivo, following oral dosing as demonstrated by pharmaco-dynamic (PD) studies examining phospho-Mer in leukemic blasts from mouse bone marrow. Kinome profiling versus more than 300 kinases in vitro and cellular selectivity assessments demonstrate that 11 has similar subnanomolar activity against Flt3, an additional important target in acute myelogenous leukemia (AML), with pharmacologically useful selectivity versus other kinases examined.

journal_name

J Med Chem

authors

Zhang W,DeRyckere D,Hunter D,Liu J,Stashko MA,Minson KA,Cummings CT,Lee M,Glaros TG,Newton DL,Sather S,Zhang D,Kireev D,Janzen WP,Earp HS,Graham DK,Frye SV,Wang X

doi

10.1021/jm500749d

subject

Has Abstract

pub_date

2014-08-28 00:00:00

pages

7031-41

issue

16

eissn

0022-2623

issn

1520-4804

journal_volume

57

pub_type

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