“Opportunities and Challenges” in the development of the HDACs drugs for cancers

Despite the popularity in the development of histone deacelytase (HDAC) inhibitors, the indications of the five already approved HDAC inhibitor drugs on the market are limited to peripheral T-cell lymphoma and cutaneous T-cell lymphoma. Unless also approved for treating T-cell lymphoma and hematoma other than myeloma, such as follicular lymphoma, the current market for HDACi cannot demonstrate this drug’s full potential.

The function of HDAC was initially discovered as to remove acetyl groups from the lysine residue at the N-terminal tail of histones. Other than deacetylating histones, more functions of HDAC were identified later: it can also act on various other non-histone proteins, including transcription factors such as RUNX3, p53, E2F, STAT, nuclear factor kappa B (NFκB), and hypoxia-inducible factor 1-α ( HIF-1α), estrogen receptor alpha (ERα), androgen receptor (AR), chaperone protein (HSP90), repair protein (Ku70), and the like.

Figure 1 Non-histone substrates for class I and II HDACs (Mariadason et al 2008)


HDACs malfunction can lead to abnormal cell activities such as gene expression, and this phenomenon has been found in various diseases. Therefore, histone deacetylase inhibitors have been extensively studied in recent years and its potential therapeutic effects have been found in many diseases. A number of HDACs have been marketed for the treatment of tumors.

Most of the HDACs inhibitors that are on the market or in the clinic are pan-HDACs inhibitors. The development of selective HDACi can reduce the side effects caused by other target activities, such as the possible toxicity of HDAC6. However, due to the large number of subtypes of HDACs and the similarity of active domains and catalytic sites in subtypes, the development of HDAC inhibitors with high subtype selectivity presents great challenge and is the future breakthrough point in research, where the efficacy will need to be verified by clinical trials. In addition, the development of dual-target HDAC inhibitors, both acting on HDACs and other targets such as PI3K, EGFR, HER2, DNA, or LSD1, is also one of the current directions. Currently, several dual-target HDAC inhibitor drugs have entered early clinical development.

HDACs function mechanism

Regulating the level of acetylation on histone lysine residues is a major function of HDACs. Histone octamers and 146 bp of DNA entangled on octamers constitute nucleosomes, which are the basic building blocks of eukaryotic chromosomes. Core histones are evolutionarily conserved. Each histone has a lysine-rich amino acid tail, and most histone modifications occur at the lysine residues at these tails. Under normal conditions, histones bind tightly to DNA. But when the lysine residues of histones are acetylated, the binding of DNA to histones is weakened, and the chromosomal structure is loose, which facilitates the binding of transcription factors and promotes transcriptional translation. HDACs can deacetylate histones and inhibit transcriptional translation.

Many experiments have shown that the abnormal expression of HDACs is associated with a variety of cancers. By analyzing the expression of HDACs in 13 types of cancers (Chronic lymphocytic leukemia, gastric cancer, breast cancer, colon cancer, liver cancer, medulloblastoma, non-small cell lung cancer, lymphoma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer and kidney cancer), 11 types of HDACs were expressed in 11 tumors. It is suggested that class I HDACs may play a key role in tumorigenesis and invasion, and may be a promising anti-tumor target.

Figure 2 epidrugs for human disease therapy (M Berdasco et al 2019)


HDACs inhibitor drug research

Due to different cellular microenvironments, the same HDACs can often affect different biological effects. Class I HDACs 1,3,8 mainly regulate cell cycle and apoptosis of cancer cells. This phenotype in cancer cells is identical to the embryonic lethal phenotype of early knockout model mice, possibly due to cell cycle disorder in knockout mouse embryonic mother cells. HDACs 8 and class II HDACs are mainly involved in the regulation of specific physiological functions such as differentiation, metastasis, cell adhesion, protein stability and related effects, and angiogenesis.

There are currently 5 HDAC inhibitor drugs on the market. Four HDAC inhibitors are approved by the US FDA for clinical treatment of peripheral T-cell lymphoma, cutaneous T-cell lymphoma, and multiple myeloma. Vorino was undergoing a phase II clinical trial for the treatment of advanced cutaneous T-cell lymphoma (CTCL) in 74 patients with stage IB or higher CTCL. Sidabenamine is an innovative drug developed by Microchip, which was approved by the CFDA in December 2014. The Phase III clinical trial of Pabisstat is a placebo with bortezomib and dexamethasone for one-to-three 3-line therapy in patients with relapsed and refractory multiple myeloma.

The five HDAC inhibitor drugs on the market are active against most of the more than 10 different subtypes of HDACs. The most selective of these is cidabenamine, which is selective for HDAC 1, 2, 3 and 10. The drugs that are still under clinical testing are mostly pan-HDAC inhibitors or partially selective HDAC inhibitors. The most selective is Entinostat, which has inhibitory activity against HDAC 1, 2 and 3 and is currently in clinical phase 3.

In addition, the dual-target HDAC inhibitor is also one of the current research directions, one drug with multiple targets. If these two (and perhaps multiple) targets are mechanically synergistic, better efficacy of the drug is expected. There are currently several dual-target HDAC inhibitors that have been clinically tested, such as Curis’ CUDC-101 (HDAC\EGFR\HER2) and CUDC-907 (HDAC\PI3K). The German pharmaceutical company 4SC’s 4SC-202 (HDAC\LSD1) and Imbrium’s Tinostamustine (HDAC\DNA) have completed clinical phase I studies, and some have entered clinical phase II trials.



1.Mariadason, & John, M. . (2008). Hdacs and hdac inhibitors in colon cancer. Epigenetics, 3(1), 28-37.

2. M Berdasco & M Esteller, Clinical epigenetics: seizing opportunities for translation, Nat. Rev. Genet, 2019, 20, 109-127.

3. Wagner, F. F., Weїwer, M., Lewis, M. C., & Holson, E. B. (2013). Small molecule inhibitors of zinc-dependent histone deacetylases. Neurotherapeutics the Journal of the American Society for Experimental Neurotherapeutics, 10(4), 589-604.