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|Ref Type||Journal Article|
|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|
|Date||2014 Aug 28|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|UNC2025||UNC-2025|UNC 2025||FLT3 Inhibitor 62 MERTK Inhibitor 13||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|