HDAC Inhibitors: Innovative Strategies for Their Design and Applications

Abstract

Histone deacetylases (HDACs) are a large family of epigenetic metalloenzymes that are involved in gene transcription and regulation, cell proliferation, differentiation, migration, and death, as well as angiogenesis. Particularly, disorders of the HDACs expression are linked to the development of many types of cancer and neurodegenerative diseases, making them interesting molecular targets for the design of new efficient drugs and imaging agents that facilitate an early diagnosis of these diseases. Thus, their selective inhibition or degradation are the basis for new therapies. This is supported by the fact that many HDAC inhibitors (HDACis) are currently under clinical research for cancer therapy, and the Food and Drug Administration (FDA) has already approved some of them. In this review, we will focus on the recent advances and latest discoveries of innovative strategies in the development and applications of compounds that demonstrate inhibitory or degradation activity against HDACs, such as PROteolysis-TArgeting Chimeras (PROTACs), tumor-targeted HDACis (e.g., folate conjugates and nanoparticles), and imaging probes (positron emission tomography (PET) and fluorescent ligands).

Single‐cell profiling guided combination therapy of c‐Fos and histone deacetylase inhibitors in diffuse large B‐cell lymphoma

“…A frequent dysregulation of HDACs in cancer cells has spurred an intense search on small molecules that inhibit them. 2 This also applies to DLBCL cells in which an overexpression of HDAC1 ties in with worse prognosis. 3 To date, five HDACs inhibitors (HDACi) have been approved by the Food and Drug Administration (FDA) USA and the FDA China for use in patients with cutaneous T cell lymphoma and multiple myeloma.…”

“… 3 To date, five HDACs inhibitors (HDACi) have been approved by the Food and Drug Administration (FDA) USA and the FDA China for use in patients with cutaneous T cell lymphoma and multiple myeloma. These are active against all four zinc‐dependent HDACs (classes I, II and IV; pan‐HDACi; Figure 1A ) or specifically target HDAC subtypes 2 , 4 (Figure 1B ). A caveat of such epigenetic drugs is that existing markers for whether tumor cells are sensitive to HDACi are often not clinically validated, and HDACi have not been applied to stratified patient groups.…”

Evaluation of the Therapeutic Potential of Histone Deacetylase 6 Inhibitors for Primary and Metastatic Uveal Melanoma

“…The hydroxamic acid (zinc binding group) pharmacophore may lead to non-selectivity as well as affecting pharmacokinetic properties [ 110 ]. To circumvent these issues, studies are focused on synthesizing novel HDACi and/or HDAC6i to present with increased affinity and/or selectivity resulting in increased efficacy and reduced toxicity [ 111 ]. Another promising solution in preclinical studies is HDACi designed as prodrugs, and HDAC6i prodrugs should be considered in UM [ 112 ].…”

Antagonistic Pharmacological Interaction between Sirtuin Inhibitor Cambinol and Paclitaxel in Triple-Negative Breast Cancer Cell Lines: An Isobolographic Analysis

“…HDACs are a large family of epigenetic metalloenzymes involved in gene transcription, cell differentiation, proliferation, migration, apoptosis or angiogenesis in cancer development and progression [ 13 ]. Sirtuins (SIRTs) belongings to IIIrd class of HDACs require NAD+ as a cofactor and include SIRT1-7 proteins in mammals [ 14 ].…”