Alex Dean

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

Blog Post created by Alex Dean on Nov 26, 2019

The development of inhibitors of Histone deacelytase (HDAC) is currently one of the hot spots, but the indications for the five drugs currently on the market are limited to the peripheral T-cell lymphoma and cutaneous T-cell lymphoma market, and the market for indications is small and the competition is relatively fierce. Unless it can develop T-cell lymphoma and hematoma other than myeloma, such as follicular lymphoma, the current market for HDACi, including existing drugs, is expected to be more of an expansion of other indications.

HDAC was first discovered to remove acetyl groups from the lysine residue at the N-terminal tail of histones. It was later discovered that HDACs not only deacetylated histones, but also acted 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)


If the activity of HDACs is abnormal, it will lead to abnormal cell activities such as gene expression, and this phenomenon has been found in various diseases. Therefore, inhibitors of histone deacetylase (HDACis) have been extensively studied in recent years and have potential therapeutic effects 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 is the future breakthrough point in actual research. It will face great challenges and the efficacy needs to be verified by clinical trials. In addition, the development of dual-target HDAC inhibitors is also one of the current directions, while acting on HDACs while acting on additional one or more other targets such as PI3K, EGFR, HER2, DNA, LSD1. Currently, several drugs have entered early clinical development.

HDACs function mechanism

Regulating the level of acetylation of 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. The 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.

A large number of experiments have shown that the abnormal expression of HDACs is associated with a variety of tumors. By analyzing the expression of HDACs in 13 tumors(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), it was found that 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 the different cellular microenvironments, the same HDACs can often affect different biological effects. Class I HDACs 1,3,8 mainly regulate the cell cycle and apoptosis of tumor cells. This phenotype in tumor 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 models HDAC drugs on the market. Four HDAC inhibitors are marketed by the US FDA for clinical treatment of peripheral T-cell lymphoma, cutaneous T-cell lymphoma, and multiple myeloma. Vorino approved 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 from 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.

HDAC has more than 10 different subtypes, and most of the HDACs of the five drugs already on the market are ubiquitous HDAC inhibitors that are active against most HDACs. The most selective of these is cidabenamine, which is selective for HDAC 1, 2, 3 and 10. The drugs in clinical practice are mostly pan-HDAC inhibitors or partially selective HDAC inhibitors. The most selective of these is Entinostat, which has the highest selectivity and 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 multiple targets. If these two (and perhaps multiple) targets are mechanically synergistic, it can be predicted that a synergistic effect will be exerted in the body to exert a better effect. 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.



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.

source: “Opportunities and Challenges” in the development of the HDACs targets for tumor drugs – BOC Sciences Blog