RGNCY-0112 (A-1592668 CDK9 inhibitor)

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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

SMILES:  FC1=CC=C(OC)C(C2=C3C([N]C(C4=CCN([C@@H]5CC[C@@H](C(O)=O)CC5)CC4)=C3)=NC=C2F)=C1

Formula: C26H26F2N3O3

Mol Wt:  466.51

PMID:  31827241

Tags: Cancer, Leukemia, Apoptosis, small molecule, hematologic, RGNCY-0112, CDK-9, A-1592668, BCL-2, MCL-1, Ser 2