What HDAC1 inhibitors are in clinical trials currently?

Introduction to HDAC1 and Its Role
Histone deacetylase 1 (HDAC1) is a key member of the class I HDAC family and plays a central role in modulating chromatin structure and gene expression. HDAC1 catalyzes the removal of acetyl groups from lysine residues on histone tails, resulting in chromatin condensation and transcriptional repression. This function is critical for regulating an array of cellular processes, including cell cycle progression, differentiation, apoptosis, and DNA repair. Over the years, research has shown that aberrant HDAC1 activity is closely linked to tumorigenesis and other diseases, making it a promising therapeutic target.

Function of HDAC1 in Cellular Processes
HDAC1’s enzymatic action modulates the acetylation status of nucleosomal histones, thereby influencing chromatin accessibility and, as a consequence, gene transcription. It is often recruited into multiprotein complexes (such as NuRD, Sin3A, and CoREST) that are essential for its deacetylase activity, fine-tuning cellular proliferation and differentiation pathways. This enzyme also participates in non‐histone protein deacetylation, thereby affecting signal transduction, DNA damage response, and cell cycle checkpoints. The ubiquity of HDAC1 means that its dysregulation may lead to altered expression of tumor suppressor genes or oncogenes, which in turn can promote tumor progression.

HDAC1 as a Therapeutic Target
Given its critical role in controlling gene expression, HDAC1 has emerged as a viable therapeutic target in a variety of diseases, particularly in cancers where uncontrolled cellular proliferation is a hallmark. Overexpression or hyperactivity of HDAC1 is frequently observed in tumors such as breast, colon, and prostate cancers, and its inhibition could restore the transcription of silenced regulatory genes. Moreover, HDAC1 is seen as a modulator of epigenetic plasticity, implying that its inhibition may reverse the aberrant epigenetic landscape associated with malignant transformation. These attributes have led to the development of HDAC inhibitors (HDACis) that target HDAC1 along with other isoforms to reinstate normal transcriptional profiles in diseased cells.

Overview of HDAC1 Inhibitors
HDAC inhibitors are a large and evolving class of small molecules that have been extensively investigated for their capacity to reactivate gene expression by modulating chromatin remodeling. While many of the currently available inhibitors are “pan‐HDAC inhibitors” affecting multiple isoforms, research over the last decade has increasingly focused on identifying compounds that either preferentially target HDAC1 or at least display high potency toward class I HDACs, including HDAC1.

Types of HDAC1 Inhibitors
The inhibitors in development or currently in clinical trials can broadly be divided into several categories:

• Pan‐HDAC Inhibitors: Drugs such as vorinostat, romidepsin, panobinostat, belinostat, and chidamide are already approved for certain hematological malignancies. Although these compounds inhibit multiple HDAC isoforms, they often exhibit significant activity toward HDAC1. However, their lack of isoform selectivity can be associated with off‐target effects and toxicities.

• Class I or Isoform‐Selective Inhibitors: Recognizing the need for higher specificity, newer agents are being developed to target class I HDACs with a particular focus on HDAC1. For example, quisinostat (JNJ-26481585) is a second-generation hydroxamic acid that has been designed to be highly potent toward HDAC1 with an IC₅₀ of approximately 0.1 nM. Another compound of interest in this category is entinostat (MS-275), a benzamide derivative that preferentially inhibits class I HDACs, including HDAC1, and is undergoing evaluation in various clinical settings. Additionally, dual inhibitors such as CUDC-101 combine HDAC inhibitory activity with the inhibition of receptor tyrosine kinases, thereby also targeting HDAC1 while engaging other oncogenic signaling pathways.

• Dual or Multi-targeting Inhibitors: Given the multifactorial nature of cancer, compounds that simultaneously target HDAC1 and key regulators in oncogenic signaling pathways have also emerged. These inhibitors (e.g., CUDC-101) offer the potential benefit of synergistic activity by blocking HDAC1-driven epigenetic repression and interfering with growth factor signaling (EGFR/HER2).

Mechanism of Action
HDAC1 inhibitors function by chelating the metal ion—typically zinc—in the catalytic site of the enzyme, thereby preventing the formation of the active deacetylase complex. Inhibition leads to hyperacetylation of histones, relaxation of chromatin structure, reactivation of silenced genes, and modulation of non-histone substrates that are critical for cell cycle arrest and apoptosis. While pan-HDAC inhibitors act on a range of HDAC isoforms, selective HDAC1 inhibitors are designed to maximize inhibition of HDAC1 activity, reducing aberrant histone deacetylation associated with malignant transformation while minimizing undesired activity on other HDACs. The design strategies include structure-based drug design and de novo reaction-mechanism-based inhibitor strategies that exploit subtle differences in the active site microenvironment between HDAC1 and other isoenzymes.

Current Clinical Trials of HDAC1 Inhibitors
Clinical trials evaluating HDAC inhibitors are numerous, although many currently in clinical practice involve pan‐HDAC inhibitors with known activity against HDAC1. Nevertheless, there is a distinct and emerging focus on agents with improved selectivity for HDAC1 or class I HDACs. The clinical trials are generally staged as Phase I, Phase II, and for some agents, Phase III trials, with the ultimate goal of establishing both safety and therapeutic efficacy in specific malignancies.

Phase I Trials
Numerous early-phase trials have examined the safety, tolerability, pharmacokinetics and pharmacodynamics of HDAC inhibitors that inhibit HDAC1 as part of their spectrum. Among these, quisinostat (JNJ-26481585) stands out for its ultra-high potency against class I HDACs, particularly HDAC1. In Phase I studies that have been conducted primarily in patients with relapsed or refractory ovarian and hematological malignancies, quisinostat has shown a promising safety profile and the ability to induce histone hyperacetylation at relatively low doses. Detailed pharmacokinetic data from these studies indicate a favorable absorption profile with consistent target engagement as measured by acetylation levels in peripheral blood mononuclear cells.

Other Phase I trials include those evaluating entinostat (MS-275), which although it is a benzamide derivative with activity against multiple class I HDACs, has shown preferential effects on HDAC1. Phase I studies of entinostat in solid tumors and hematological malignancies have helped to fine-tune its dosing regimen while assessing toxicity profiles dominated primarily by manageable hematologic toxicities and fatigue. Furthermore, dual-action compounds such as CUDC-101, which inhibit HDAC1 along with receptor tyrosine kinases, are also in Phase I trials aimed at determining the maximum tolerated dose and assessing preliminary anti-tumor activity.

These Phase I evaluations not only address the drug’s safety profile but also exploit pharmacodynamic biomarkers such as changes in histone acetylation levels to confirm evidence of target engagement. The collection of these early data is critical to establishing dose recommendations for subsequent Phase II studies. Importantly, the early-phase trial results underscore the necessity of achieving sufficient selectivity for HDAC1 to mitigate off-target toxicities frequently associated with pan-inhibition.

Phase II Trials
Phase II trials for HDAC inhibitors aim to establish therapeutic efficacy in a more homogeneous patient population. Although many agents tested in these phases remain broad-spectrum HDAC inhibitors, there is an emerging trend to include agents with improved selectivity toward class I HDACs, including HDAC1. Quisinostat, by virtue of its high potency against HDAC1, continues to advance into Phase II trials where its efficacy is being evaluated in both hematological malignancies and solid tumors such as glioblastoma and ovarian cancers. In these trials, endpoints such as progression-free survival, overall survival, and objective response rates are being assessed along with detailed toxicity evaluations.

Additionally, entinostat has entered Phase II studies in various solid tumor indications. These studies are designed to evaluate not only its single-agent efficacy but also its potential synergistic effects when combined with other therapeutics, such as immunotherapy (checkpoint inhibitors) or chemotherapeutic agents. The rationale is that selectively inhibiting HDAC1 may reverse epigenetic silencing of tumor suppressor genes and enhance the susceptibility of cancer cells to immunomodulatory or cytotoxic drugs. Dual inhibitors like CUDC-101 are also being examined in Phase II settings, especially in cancers overexpressing HDAC1 along with aberrant receptor signaling pathways. Early results indicate that the dual action of these agents can translate into improved anti-tumor activity and a more favorable toxicity profile compared to non-selective HDAC inhibition.

While the majority of ongoing Phase II trials still involve compounds that target multiple HDAC isoforms, there is a clear momentum toward evaluating agents that offer the promise of reduced toxicity through enhanced isoform specificity. Given that HDAC1 is intimately involved in tumor cell proliferation and survival, these trials are expected to inform which specific HDAC1 inhibitory profiles yield the best clinical outcomes with manageable adverse events.

Phase III Trials
At this point, the number of Phase III trials focusing exclusively on isoform-selective HDAC1 inhibitors remains limited because of the challenges inherent in developing molecules with high isoform specificity. The currently approved HDAC inhibitors in clinical use for cancer therapy (vorinostat, romidepsin, panobinostat, belinostat, and chidamide) are predominantly pan-HDAC inhibitors, and while they all inhibit HDAC1 among other isoforms, they are not selective for HDAC1. Consequently, Phase III trials involving these agents are designed for broader indications rather than testing HDAC1-specific inhibition.

Nevertheless, there is an anticipation in the field that as more data become available from early-phase studies—especially with compounds such as quisinostat and entinostat—subsequent Phase III trials may be designed to evaluate the therapeutic benefit of HDAC1-targeted therapy in specific patient cohorts. These trials will likely focus on indications where HDAC1 overexpression is clearly linked to disease progression, such as certain subtypes of breast, ovarian, and hematological cancers. The transition to Phase III trials will also depend on refined patient stratification based on molecular biomarkers that predict responsiveness to HDAC1 inhibition, which in turn could facilitate better clinical outcomes and reduced toxicity.

Potential Applications and Challenges
While the primary motivation for developing HDAC1 inhibitors is their potential anti-tumor activity, their utility extends to a range of therapeutic areas. At the same time, clinical development is fraught with a number of challenges that must be navigated carefully.

Therapeutic Areas
HDAC1 inhibitors are being investigated in a variety of cancer types where aberrant epigenetic regulation plays a central role in tumorigenesis. The major therapeutic areas include:

• Solid Tumors: Clinical trials involving agents like quisinostat are broadening our understanding of HDAC1 inhibition in solid tumors, including ovarian cancer, glioblastoma, and breast cancer. The ability of HDAC1 inhibitors to reverse epigenetic silencing of tumor suppressor genes is thought to render these tumors more amenable to both monotherapy and combination strategies.

• Hematological Malignancies: Given that several hematologic cancers exhibit deregulated HDAC1 activity, inhibitors such as entinostat are being evaluated for their ability to induce cell cycle arrest and apoptosis in lymphomas and leukemias. Early-phase trials have focused on patient populations with relapsed or refractory diseases, where conventional therapies have failed.

• Combination Therapies: An emerging trend is the use of HDAC1 inhibitors in combination with immunotherapies, targeted therapies, or conventional chemotherapeutic agents. By sensitizing cancer cells through epigenetic modulation, HDAC1 inhibitors can potentially enhance the efficacy of other drugs while allowing for lower doses to be used, thereby reducing adverse side effects.

• Other Non-Oncology Indications: Although the majority of clinical trials currently focus on oncology, preclinical studies suggest that selective modulation of HDAC1 activity might benefit neurodegenerative diseases and inflammatory conditions. However, these applications are at an earlier stage of investigation compared to oncology.

Challenges in Clinical Development
The development of HDAC1 inhibitors faces several significant challenges that are being actively addressed by the research community:

• Isoform Selectivity: Achieving selectivity for HDAC1 over other HDACs is difficult because of the high sequence and structural similarity within the class I family. Most current inhibitors exhibit a broad spectrum of activity, which contributes to systemic toxicities. Advanced design strategies, including structure-based drug design and de novo reaction-mechanism-based methodologies, are being developed to overcome these challenges.

• Toxicity and Off-Target Effects: Pan-HDAC inhibition is associated with side effects ranging from hematologic toxicities (e.g., thrombocytopenia, lymphopenia, neutropenia) to gastrointestinal disturbances and fatigue. Isoform-selective inhibitors such as quisinostat and entinostat are being engineered with the hope of mitigating these effects. However, long-term safety data are still emerging, and further refinements in drug design and dosing regimens will be necessary.

• Patient Stratification and Biomarkers: The heterogeneous nature of tumors means that not all patients will respond equally to HDAC1 inhibition. Ongoing clinical trials are incorporating biomarkers—such as histone acetylation levels and HDAC1 expression profiles—to help stratify patients and predict therapeutic response. However, the clinical utility of these biomarkers in routine practice remains to be fully validated.

• Pharmacokinetics and Bioavailability: Ensuring that sufficient drug concentrations reach the tumor site while minimizing systemic distribution is crucial. Phase I trials of agents like quisinostat have provided encouraging pharmacokinetic data, but further work is needed to optimize bioavailability and minimize off-target accumulation.

• Combination Strategy Complexity: While combination regimens offer potential synergistic effects, they also add layers of complexity in terms of dosing, drug–drug interactions, and compounded toxicities. Clinical trials combining HDAC1 inhibitors with other agents must carefully balance efficacy with the potential for adverse interactions.

Future Directions and Conclusions
Ongoing research continues to refine the approach to HDAC1 inhibition. The next generation of inhibitors is expected to offer enhanced potency and selectivity, along with improved pharmacokinetic profiles, which in turn should translate into better clinical outcomes and reduced toxicity. Preclinical studies emphasize the need for a deeper molecular understanding of the interplay between HDAC1 and its downstream signaling pathways, which will guide the development of more predictive biomarkers and patient stratification strategies.

Emerging Trends in HDAC1 Inhibition
Several promising trends are emerging in the field of HDAC1 inhibitor development:

• Enhanced Selectivity Through Rational Design: Advances in computational modeling, including de novo reaction-mechanism-based design approaches, are enabling the development of inhibitors with enhanced selectivity for HDAC1 over other isoforms. For example, quisinostat has been designed to exploit subtle differences in the active site environment, leading to its ultra-high potency against HDAC1.

• Dual and Multi-targeting Agents: Given the multifactorial nature of cancer, dual inhibitors such as CUDC-101 have been developed to simultaneously target HDAC1 and key signaling kinases like EGFR and HER2. This polypharmacological approach may allow for synergistic inhibition of tumor growth and improved patient outcomes with diminished risks of resistance.

• Combination Treatment Strategies: Future clinical trials are likely to focus increasingly on combination therapies that integrate HDAC1 inhibitors with immunotherapeutic agents (for example, PD-1 inhibitors), chemotherapeutic drugs, or targeted therapies. These combination regimens are being designed not only to improve response rates but also to overcome drug resistance mechanisms inherent in many cancers.

• Biomarker-Driven Clinical Development: The integration of predictive biomarkers into clinical trial design is emerging as an essential component of HDAC1 inhibitor development. Biomarkers such as histone acetylation levels, HDAC1 expression profiles, and gene expression signatures associated with epigenetic dysregulation are already being used in early-phase trials to stratify patients and tailor treatment.

• Investigational Platforms and Nanotechnology: Innovative drug delivery systems, including nanoparticle-based platforms, are being explored to enhance the bioavailability of HDAC1 inhibitors and improve their target specificity. Such technologies may help to minimize systemic toxicity and allow for more precise tumor targeting.

Summary of Key Findings
In summarizing the landscape of HDAC1 inhibitors in the context of current clinical trials, several key points emerge. First, while the clinical pipeline for HDAC inhibitors has traditionally been dominated by pan-HDAC inhibitors—including vorinostat, romidepsin, panobinostat, belinostat, and chidamide—there is a growing body of evidence supporting the need for isoform-selective compounds. These selective inhibitors, exemplified by quisinostat (JNJ-26481585) and entinostat (MS-275), show potent activity against HDAC1 and are currently undergoing Phase I and Phase II trials in both hematological malignancies and solid tumors.

Second, current Phase I trials focus on defining the safety, tolerability, and pharmacodynamic markers of these selective inhibitors, with promising results indicating robust target engagement and manageable toxicity profiles. Phase II trials are actively assessing the efficacy of these compounds, both as monotherapies and in combination regimens, while Phase III evaluations remain limited primarily due to the challenges of achieving high isoform selectivity without compromising clinical efficacy.

Third, HDAC1 inhibitors are being explored across diverse therapeutic areas—from ovarian and breast cancers to glioblastomas and certain hematological malignancies—underscoring the broad relevance of HDAC1 in oncogenesis. Concurrently, significant challenges remain regarding off-target effects, optimal dosing, and patient selection, all of which require continued research and carefully designed clinical trials.

In conclusion, while the current clinical trial landscape features many compounds with activity against HDAC1, the movement toward developing inhibitors that are more selective for HDAC1 is gaining momentum. Quisinostat and entinostat serve as paradigmatic examples of this new generation of HDAC1-targeted agents that promise enhanced efficacy and safety. Future clinical studies are expected to refine these approaches further through advanced biomarker integration, innovative combination strategies, and state-of-the-art drug delivery systems, ultimately paving the way for more personalized and effective cancer therapies. These developments, supported by robust preclinical modeling and early-phase clinical data, underscore the potential of HDAC1 inhibitors to become a cornerstone in the evolving paradigm of epigenetic cancer therapy.

Overall, through a general framework that moves from broad preclinical understanding to specific early clinical evaluations and ultimately targeted therapeutic applications, the current clinical trials of HDAC1 inhibitors reflect both the promise and the complexity of translating epigenetic modulation into effective treatments. The promise of high selectivity to limit adverse effects and the integration of HDAC1 inhibitors into combination regimens herald an exciting era in cancer treatment. However, significant challenges related to toxicity, patient stratification, and achieving sustained therapeutic efficacy remain. The future will likely see a convergence of improved molecular designs, precision diagnostics, and innovative clinical trial designs that together enhance the therapeutic index of HDAC1 inhibitors and expand their use across a broader range of malignancies.

In summary, while pan‐HDAC inhibitors continue to be a critical component of the current therapeutic arsenal, emerging HDAC1-selective agents—most notably quisinostat and entinostat—are poised to offer improved outcomes due to their refined target specificity. Their progression through Phase I and Phase II clinical trials, along with evolving combination strategies and biomarker-driven patient selection, underscores a significant shift toward personalized medicine in the field of epigenetic therapeutics. With continued research and further Phase III evaluations, HDAC1 inhibitors could eventually achieve regulatory approval as stand-alone treatments or in combination, marking a pivotal step forward in cancer treatment and potentially other indications influenced by epigenetic dysregulation.