What is the mechanism of Entinostat?

Entinostat is a potent and selective inhibitor of class I histone deacetylases (HDACs), specifically targeting HDAC1 and HDAC3. These HDACs play a crucial role in the regulation of gene expression by modulating the acetylation status of histones, which are proteins around which DNA is wrapped. The acetylation and deacetylation of histones are key processes that determine the accessibility of chromatin and thus influence gene transcription.

Histone acetylation generally correlates with an open chromatin structure and active gene transcription. In contrast, histone deacetylation is associated with a closed chromatin conformation and gene repression. By inhibiting HDACs, entinostat increases the acetylation levels of histones, leading to a more relaxed chromatin structure and changes in gene expression patterns.

One of the primary mechanisms by which entinostat exerts its effects is through the reactivation of tumor suppressor genes. In many cancers, these genes are silenced due to hypoacetylation of histones and subsequent chromatin compaction. By inhibiting HDAC1 and HDAC3, entinostat restores the acetylation of histones, thereby reactivating these crucial genes and inhibiting cancer cell growth.

In addition to its effects on histones, entinostat also impacts non-histone proteins. Many transcription factors, signaling molecules, and other proteins undergo acetylation and deacetylation, which can influence their stability, localization, and activity. By altering the acetylation of these proteins, entinostat can modulate various cellular processes involved in cancer progression, including cell cycle regulation, apoptosis, and differentiation.

One of the significant therapeutic potentials of entinostat is its ability to enhance the efficacy of other anticancer treatments. For instance, entinostat has been shown to increase the sensitivity of cancer cells to hormone therapies, chemotherapy, and immune checkpoint inhibitors. This synergistic effect is due to entinostat's capacity to modulate the tumor microenvironment, enhance immune responses, and reduce the expression of proteins involved in drug resistance.

Entinostat is also known to induce cell cycle arrest and promote apoptosis in cancer cells. By increasing the expression of cyclin-dependent kinase inhibitors like p21 and p27, entinostat can halt cell cycle progression, thereby preventing cancer cell proliferation. Furthermore, entinostat can activate intrinsic apoptotic pathways, leading to programmed cell death in cancer cells.

Clinical studies have shown promising results for entinostat in various types of cancer, including breast cancer, lung cancer, and colorectal cancer. Its safety profile and efficacy as part of combination therapies make it a valuable agent in the ongoing battle against cancer.

In summary, entinostat is a selective HDAC inhibitor that exerts its anticancer effects through the reactivation of tumor suppressor genes, modulation of non-histone protein functions, enhancement of other anticancer treatments, and induction of cell cycle arrest and apoptosis. Its multifaceted mechanisms of action underscore its potential as a versatile and powerful tool in oncology.