2. Academic Validation
  3. UNC2025, a potent and orally bioavailable MER/FLT3 dual inhibitor

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

  • J Med Chem. 2014 Aug 28;57(16):7031-41. doi: 10.1021/jm500749d.
Weihe Zhang 1,  Deborah DeRyckere,  Debra Hunter,  Jing Liu,  Michael A Stashko,  Katherine A Minson,  Christopher T Cummings,  Minjung Lee,  Trevor G Glaros,  Dianne L Newton,  Susan Sather,  Dehui Zhang,  Dmitri Kireev,  William P Janzen,  H Shelton Earp,  Douglas K Graham,  Stephen V Frye,  Xiaodong Wang
Affiliations

Affiliation

  • 1 Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, ‡Department of Pharmacology, School of Medicine, and §Lineberger Comprehensive Cancer Center, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
PMID: 25068800 DOI: 10.1021/jm500749d
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.

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