BRD0705

BRD0705 is a potent, paralog selective and orally active GSK3α inhibitor with an IC₅₀ of 66 nM and a K_d of 4.8 μM. BRD0705 displays increased selectivity for GSK3α (8-fold) versus GSK3β (IC₅₀ of 515 nM). BRD0705 can be used for acute myeloid leukemia (AML) research^[1]. In Vitro: BRD0705 displays excellent selectivity in a penal of 311 kinases, the CDK family of kinases (CDK2, 3 and 5) are next most potently inhibits at values of 6.87 μM, 9.74 μM and 9.20 μM (87-fold, 123-fold and 116-fold selectivity relative to GSK3α)^[1].
BRD0705 (10-40 μM; 2-24 hours; U937 cells) treatment impairs GSK3α Tyr279 phosphorylation in a time-and concentration-dependent manner without affecting GSK3β Tyr216 phosphorylation^[1].
Using a β-catenin dependent TCF/LEF luciferase reporter assay, the absence of β-catenin induced target activation after treatment with BRD0705 in AML cell lines^[1].
BRD0705 impairs AML colony formation in all six tested cell lines, MOLM13, TF-1, U937, MV4-11, HL-60 and NB4, in a concentration-dependent manner, as opposed to BRD3731 which impairs colony formation in TF-1 while increasing colony forming ability in the MV4-11 cell line^[1]. In Vivo: BRD0705 (30 mg/kg; oral gavage; twice daily; NSG mice) treatment impairs leukemia initiation and prolongs survival in AML mouse models^[1].