RGNCY-0112 (A-1592668 CDK9 inhibitor)
A-1592668 is a potent, orally active CDK9 inhibitor with a selectivity profile distinct from related molecules that have been clinically studies. In short-term treatment studies, A-1592668 rapidly downregulates RNA pol-II (Ser 2) phosphorylation resulting in the loss of MCL-1 protein and apoptosis in MCL-1-dependent hematologic tumor cell lines. The resultant ell death could be attenuated by inhibiting caspases or overexpressing BCL-2 protein.In a number of hematologic cell lines and primary NHL patient samples, synergisic cell killing was demonstrated between A-1592668 and venetoclax. The combination treatment of A-1592668 and venetoclax was well tolerated in vivo and showed efficacy well above to either treatment alone in murine models of lymphoma and AML. CDK9 IC50 = 1.2nM, H929 IC50 = 39nM, MV4-11 IC50 = 42.4nM.
Systematic Name: (1r,4r)-4-(4-(5-fluoro-4-(5-fluoro-2-methoxyphenyl)-1l2-pyrrolo[2,3-b]pyridin-2-yl)-3,6-dihydropyridin-1(2H)-yl)cyclohexane-1-carboxylic acid
Mol Wt: 466.51
Tags: Cancer, Leukemia, Apoptosis, small molecule, hematologic, RGNCY-0112, CDK-9, A-1592668, BCL-2, MCL-1, Ser 2