A Comprehensive Review of Vorinostat (Suberoylanilide Hydroxamic Acid): A First-in-Class Histone Deacetylase Inhibitor

Abstract

Vorinostat, also known as suberoylanilide hydroxamic acid (SAHA), is a first-in-class, orally bioavailable small molecule that functions as a pan-histone deacetylase (HDAC) inhibitor. Its primary mechanism of action involves the chelation of a zinc ion within the catalytic site of Class I, II, and IV HDACs, leading to enzymatic inhibition. This results in the hyperacetylation of core nucleosomal histones and other non-histone proteins, which promotes a more open chromatin structure and alters the expression of a subset of genes critical for cell cycle control, differentiation, and apoptosis. This report details the scientific and clinical profile of Vorinostat. On October 6, 2006, Vorinostat, under the brand name Zolinza®, received landmark approval from the U.S. Food and Drug Administration (FDA) for the treatment of cutaneous manifestations in patients with progressive, persistent, or recurrent cutaneous T-cell lymphoma (CTCL) following two systemic therapies. This approval was based on a pivotal Phase IIb study demonstrating an objective response rate of approximately 30%. Beyond its approved indication, Vorinostat has been extensively investigated across a broad spectrum of other malignancies, including solid tumors and hematologic cancers, typically in combination with other anticancer agents, and as a latency-reversing agent in HIV infection research. The characteristic safety profile of Vorinostat is manageable but significant, dominated by fatigue, gastrointestinal toxicities (diarrhea, nausea), and myelosuppression (thrombocytopenia, anemia). As a foundational epigenetic therapeutic, Vorinostat has not only provided a valuable treatment option for a rare cancer but has also validated HDACs as a therapeutic target, paving the way for the development of an entire new class of anticancer drugs.