BRD0705

• CAT Number: I017641
• CAS Number: 2056261-41-5
• Molecular Formula: C20H23N3O
• Molecular Weight: 321.42
• Purity: ≥95%
• Synonyms: (4S)-4-ethyl-7,7-dimethyl-4-phenyl-1,6,8,9-tetrahydropyrazolo[3,4-b]quinolin-5-one
• InChI: InChI=1S/C20H23N3O/c1-4-20(13-8-6-5-7-9-13)14-12-21-23-18(14)22-15-10-19(2,3)11-16(24)17(15)20/h5-9,12H,4,10-11H2,1-3H3,(H2,21,22,23)/t20-/m0/s1
• InChIKey: NCKLQXXBRWCYMA-FQEVSTJZSA-N
• SMILES: CCC1(C2=C(NC3=C1C(=O)CC(C3)(C)C)NN=C2)C4=CC=CC=C4

BRD0705 is a potent, paralog selective and orally active GSK3α inhibitor with an IC50 of 66 nM and a Kd 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].
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].
BRD0705 (30 mg/kg; oral gavage; twice daily; NSG mice) treatment impairs leukemia initiation and prolongs survival in AML mouse models[1].

Reference

[1]. Wagner FF, et al. Exploiting an Asp-Glu “switch” in glycogen synthase kinase 3 to design paralog-selective inhibitors for use in acute myeloid leukemia. Sci Transl Med. 2018 Mar 7;10(431). pii: eaam8460.
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