Abexinostat

Abexinostat (CRA 024781) is a novel pan-HDAC inhibitor mostly targeting HDAC1 with K_i of 7 nM. Abexinostat also inhibits metallo-β-lactamase domain-containing protein?2 (MBLAC2) hydrolase activity with an EC₅₀ below 10 nM^[1][4]. IC50 & Target: Ki: 7 nM (HDAC1); 8.2 nM (HDAC3)^[1] In Vitro: Abexinostat (CRA 024781) exhibits potent antitumor activity against a variety of tumor cell lines with GI_50% ranging from 0.15 μM to 3.09 μM. Abexinostat (CRA 024781) also has an antiproliferative effect on HUVEC endothelial cells with GI_50% of 0.43 μM. Abexinostat (CRA 024781) treatment causes dose-dependent accumulation of both acetylated histones and acetylated tubulin in HCT116 or DLD-1 cells, induces expression of p21, and leads to PARP cleavage and accumulation of the γH2AX^[1]. Inhibition of HDAC enzymes by Abexinostat (CRA 024781) leads to a significant reduction in the transcription of genes specifically associated with HR, including RAD51. Consistent with inhibition of HR, Abexinostat (CRA 024781) treatment results in a decreased ability to perform homology directed repair of I-SceI-induced chromosome breaks in transfected CHO cells^[2]. Abexinostat (CRA 024781) induces S phase depletion, G2 cell cycle arrest, and apoptosis in soft tissue sarcoma (STS) cells. Abexinostat (CRA 024781) induces Rad51 transcriptional repression in STS cells potentially mediated via enhanced E2F1 binding to the Rad51 proximal promoter^[3]. In Vivo: Abexinostat (CRA 024781) parenterally administered to mice harboring HCT116 or DLD-1 colon tumor xenografts results in a statistically significant reduction in tumor growth. Inhibition of tumor growth is accompanied by an increase in the acetylation of α-tubulin in peripheral blood mononuclear cells, and an alteration in the expression of many genes in the tumors, including several involved in apoptosis and cell growth^[1].