UNC2025, a Potent and Orally Bioavailable MER/FLT3 Dual Inhibitor

作者：Zhang Weihe; DeRyckere Deborah; Hunter Debra; Liu Jing; Stashko Michael A; Minson Katherine A; Cummings Christopher T; Lee Minjung; Glaros Trevor G; Newton Dianne L; Sather Susan; Zhang Dehui; Kireev Dmitri; Janzen William P; Earp H Shelton; Graham Douglas K; Frye Stephen V^*; Wang Xiaodong

来源：Journal of Medicinal Chemistry, 2014, 57(16): 7031-7041.

DOI：10.1021/jm500749d

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.

• 出版日期2014-8-28