entinostat

Entinostat, also known as MS-275, is an oral small-molecule histone deacetylase inhibitor (HDACi) that belongs to the benzamide class. It is a selective inhibitor of class I histone deacetylases, with potent activity against HDAC1 and HDAC3 and weaker activity against HDAC2 and HDAC6.

Mechanism: HDAC inhibition leads to increased acetylation of histones and non-histone proteins, resulting in changes in gene expression that can suppress tumor growth, induce cell cycle arrest and apoptosis, and enhance differentiation. Entinostat may also modulate the tumor immune microenvironment by affecting regulatory T cells and antigen presentation, which has prompted investigation in combination with immunotherapies.

Clinical development: Entinostat has been studied in various solid tumors and hematologic cancers, most notably in hormone receptor–positive, HER2-negative advanced breast cancer in combination with exemestane in a phase III trial (E2112). The trial did not meet its primary endpoint of overall survival. Other early-phase trials have explored combinations with immune checkpoint inhibitors, chemotherapy, and targeted therapies.

Chemistry and availability: As a benzamide HDAC inhibitor, entinostat is typically administered orally in clinical settings. It has not been approved by major regulatory agencies for any indication, and clinical development continues primarily in trial contexts. Common adverse events observed include fatigue, nausea, diarrhea, decreased appetite, and cytopenias.