AR-42 is an HDAC inhibitor with IC50 of 30 nM. Phase 1.Greater potency relative to SAHA.
The growth of PC-3 tumor xenografts is suppressed by 52% and 67% after treatment with AR-42 at 25 mg/kg and 50 mg/kg, respectively, whereas SAHA at 50 mg/kg suppresses growth by 31%. In contrast to mice treated with SAHA, intratumoral levels of phospho-Akt and Bcl-xL are markedly reduced in AR-42 treated mice. In the transgenic adenocarcinoma of the mouse prostate (TRAMP) model, administration of AR-42 not only decreases the severity of prostatic intraepithelial neoplasia (PIN) and completely prevents its progression to poorly differentiated carcinoma, but also shifts tumorigenesis to a more differentiated phenotype, suppressing absolute and relative urogenital tract weights by 86% and 85%, respectively. AR-42 significantly reduces leukocyte counts, and prolongs survival in three separate mouse models of B-cell malignancy without evidence of toxicity. |
