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Ref Type Journal Article
PMID (25068800)
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
Title UNC2025, a potent and orally bioavailable MER/FLT3 dual inhibitor.
Journal Journal of medicinal chemistry
Vol 57
Issue 16
Date 2014 Aug 28
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
UNC2025 UNC2025 1 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
UNC2025 UNC-2025|UNC 2025 FLT3 Inhibitor 55 MERTK Inhibitor 9 UNC2025 inhibits FLT3 and MERTK, which may result in decreased growth of MER-dependent and FLT3-dependent tumor cells (PMID: 25068800, PMID: 30482852).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FLT3 mutant acute myeloid leukemia sensitive UNC2025 Preclinical Actionable In a preclinical study, UNC2025 inhibited FLT3 activation and growth of acute myeloid leukemia cells harboring a FLT3-ITD mutation in culture (PMID: 25068800). 25068800