AN446

AN446 is a novel histone deacetylase inhibitor (HDACI) prodrug, chemically characterized as a valproic acid derivative (valproate-valpromide of acyclovir prodrug)[2][1]. It is metabolized by cellular esterases, particularly active in cancer cells, to release valproic acid, an established HDAC inhibitor. AN446 shows selective HDAC inhibitory activity, being more potent in cancer cells than normal cells, and demonstrates anticancer efficacy in preclinical models, especially in triple-negative breast cancer (TNBC) and glioblastoma[1][2][4][10]. It synergizes with doxorubicin (Dox), increasing anti-tumor activity while reducing toxic side effects, including doxorubicin-induced cardiotoxicity. Mechanistically, AN446 induces unique acetylation and methylation of histones, alters tumor gene expression, decreases SIRT1, COX2, collagen I, c-MYC, and RAD51 in tumors, thereby reducing fibrosis, viability, inflammation, and metastasis. AN446 is considered a promising candidate for TNBC due to these properties[2][1][10].