KB-0742 dihydrochloride

• CAT Number: I044665
• CAS Number: 2416874-75-2
• Molecular Formula: C16H27Cl2N5
• Molecular Weight: 360.33
• Purity: ≥95%
• Synonyms: (1S,3S)-3-N-(5-pentan-3-ylpyrazolo[1,5-a]pyrimidin-7-yl)cyclopentane-1,3-diamine;dihydrochloride
• InChI: InChI=1S/C16H25N5.2ClH/c1-3-11(4-2)14-10-16(19-13-6-5-12(17)9-13)21-15(20-14)7-8-18-21;;/h7-8,10-13,19H,3-6,9,17H2,1-2H3;2*1H/t12-,13-;;/m0../s1
• InChIKey: OTUPXOLLHVLWQF-NJHZPMQHSA-N
• SMILES: CCC(CC)C1=NC2=CC=NN2C(=C1)NC3CCC(C3)N.Cl.Cl

KB-0742 dihydrochloride is a potent, selective and orally active CDK9 inhibitor with an IC50 of 6 nM for CDK9/cyclin T1. KB-0742 dihydrochloride is selective for CDK9/cyclin T1 with >50-fold selectivity over other CDK kinases. KB-0742 dihydrochloride has potent anti-tumor activity[1].
KB-0742 (6 hours; 0.1-10 μM; 22Rv1 cells) treatment significant reduction of downstream phosphorylation of RNA Pol II at Ser2 and Ser7, and diminished phosphorylation at Ser5. Global androgen receptor (AR)-FL and AR-V protein levels are significantly reduced starting at 6 h treatment time, which is accompanied by the reduction of phospho-AR levels (Ser81)[1].
KB-0742 (48-72 hours) treatment shows cytostatic effects in prostate cancer and leukemia cell lines. KB-0742 shows antiproliferative activity with GR50s of 0.183 μM and 0.288 μM for 22Rv1 cells and MV-4-11 AML cells, respectively[1].
In 22Rv1 cells, KB-0742 rapidly downregulates nascent transcription, preferentially depleting short half-life transcripts and AR-driven oncogenic programs[1].
KB-0742 (3-30 mg/kg; p.o.; daily; over 21 days) is well tolerated even at high dose, while significantly reducing tumor burden in 22Rv1 human prostate cancer cell line-derived xenograft (CDX) models[1].

Reference

[1]. André Richters, et al. Modulating Androgen Receptor-Driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors. Cell Chem Biol. 2020 Oct 20;S2451-9456(20)30380-9.
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