Open AccessUNC2025, a Potent and Orally Bioavailable MER/FLT3 Dual Inhibitor
Author(s) -
Weihe Zhang,
Deborah DeRyckere,
Debra M. Hunter,
Jing Liu,
Michael A. Stashko,
Katherine A. Minson,
Christopher T. Cummings,
Minjung Lee,
Trevor Glaros,
Dianne L. Newton,
Susan Sather,
Dehui� Zhang,
Dmitri Kireev,
William P. Janzen,
H. Shelton Earp,
Douglas K. Graham,
Stephen V. Frye,
Xiaodong Wang
Publication year - 2014
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/jm500749d
Subject(s) - kinome , chemistry , in vivo , pharmacology , kinase , bioavailability , tyrosine kinase inhibitor , in vitro , dasatinib , tyrosine kinase , biochemistry , signal transduction , cancer , medicine , biology , microbiology and biotechnology
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.
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