Stenoparib (E7449)

Description: E7449 (also known as 2X-121) is a novel, potent and orally available small molecule inhibitor of PARP1 and PARP2 nuclear enzymes poly (ADP-ribose) polymerase which also inhibits TNKS1 and TNKS2, with IC50s of 2.0, 1.0, ?50 and ?50 nM for PARP1, PARP2, TNKS1 and TNKS2, respectively, using 32P-NAD+ as substrate. It has potential antineoplastic activity. E7449 inhibits PARP enzymatic activity and additionally traps PARP1 onto damaged DNA; a mechanism previously shown to augment cytotoxicity. Cells deficient in DNA repair pathways beyond homologous recombination were sensitive to E7449 treatment. Chemotherapy was potentiated by E7449 and single agent had significant antitumor activity in BRCA-deficient xenografts. Additionally, E7449 inhibited Wnt/beta-catenin signaling in colon cancer cell lines, likely through TNKS inhibition. Consistent with this possibility, E7449 stabilized axin and TNKS proteins resulting in beta-catenin de-stabilization and significantly altered expression of Wnt target genes. Notably, hair growth mediated by Wnt signaling was inhibited by E7449. A pharmacodynamic effect of E7449 on Wnt target genes was observed in tumors, although E7449 lacked single agent antitumor activity in vivo, a finding typical for selective TNKS inhibitors. E7449 antitumor activity was increased through combination with MEK inhibition. Particularly noteworthy was the lack of toxicity, most significantly the lack of intestinal toxicity reported for other TNKS inhibitors. E7449 represents a novel dual PARP1/2 and TNKS1/2 inhibitor which has the advantage of targeting Wnt/beta-catenin signaling addicted tumors. E7449 is currently in early clinical development.

References: Oncotarget. 2015 Dec 1; 6(38):41307-23.