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 Chemjournal_title
Journal of medicinal chemistryauthors
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 Xdoi
10.1021/jm500749dsubject
Has Abstractpub_date
2014-08-28 00:00:00pages
7031-41issue
16eissn
0022-2623issn
1520-4804journal_volume
57pub_type
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