Epigenetic regulatory mechanisms represent attractive targets for new therapeutic approaches to a variety of human health problems due to the global nature of gene expression modification achieved through their use. Histone deacetylase (HDAC) inhibitors (HDACi) have been approved for use in the treatment of certain T-cell lymphomas, but class I HDACi have been shown to do the following:
Also, currently approved HDACi have significant toxicity, which is not acceptable for the treatment of chronic, nonlethal disease. Cetya’s HDAC inhibitor portfolio includes 30+ compounds and provides a systematic approach to developing class I HDACi with an acceptable toxicity profile to treat chronic disorders.
HDAC inhibitors have been shown to have both pro- and anti-inflammatory effects, depending on the immune activation status of the model system, the isoform selectivity of the HDACi and the timing of the delivery of the HDACi compared to the immune stimulus provided. Class I HDACi, such as the type under development at Cetya, enhance natural killer cell function and synergize with checkpoint inhibitors such as anti-PD1 antibodies.
Hemoglobinopathies such as sickle cell disease and β-thalassemias are characterized by defects in the adult form of hemoglobin in these patients, although the fetal form of hemoglobin in these patients is typically not defective in any way. Therefore, it is hypothesized that increasing the expression level of fetal hemoglobin, which is downregulated shortly after birth, will provide additional oxygen-carrying capacity to the blood and mitigate the symptoms of these disorders.
Recent studies have shown that class I HDACs play a role in the complex that suppresses fetal hemoglobin expression shortly after birth. The use of class I HDACi, such as those in Cetya’s compound portfolio, causes the complex to fall apart resulting in increased fetal hemoglobin expression.
Cetya has early data showing that fetal hemoglobin expression can be increased two- to three-fold without cellular toxicity upon exposure to certain largazole analogs. The lack of toxicity is an important criterion for any drug therapy that would require regular use to treat these chronic conditions.
Chronic inflammatory diseases such as rheumatoid arthritis are characterized by periodic episodes of inflammation driven in part by the systematic release of cytokines (i.e., cytokine storms). Central to this process is the macrophage, a phagocytic white blood cell that is part of the innate immune response. Resting macrophages are activated following exposure to either TNF-α or interferon-γ. These activated macrophages then react to certain stimuli, such as endotoxin, by releasing various cytokines that drive the cytokine storm that results in local inflammation.
Class I histone deacetylase (HDAC) inhibitors (HDACi) have been shown to have both pro- and anti-inflammatory activities. Cetya’s HDACi portfolio of 30+ compounds allows a systematic approach to developing class I HDACi that maximize anti-inflammatory activity. The largazole-based scaffold provides a building block for a directed structure-activity relationship (SAR) lead optimization program. The development program will be based on the specific biological readouts of macrophage activation and cytokine secretion. In addition, currently approved HDAC inhibitors such as vorinostat and romidepsin have significant toxicities that are unacceptable for treatment of a chronic, nonlethal disease.
The macrocyclic ring within the largazole structure can be modified in multiple places to incorporate a targeting moiety, allowing the resulting derivative to target a cell type of interest; in this case, use of a high-mannose group to access resting macrophages through the mannose receptor. Targeting is the classic approach to reduce toxicity, the driver of monoclonal antibody therapy as well as alternate formulation strategies such as liposomes or nanoparticles.
This systematic approach provides the opportunity to utilize HDACi for the treatment of chronic disorders where, to date, their use has not been feasible due to systemic toxicities.
Cancer remains a major unmet medical need, both in the US and worldwide. The American Cancer Society estimates that over 1.7 million people in the US will be diagnosed with cancer in 2018, and roughly 610,000 deaths from cancer will occur1; one in five people in the US will die of cancer2.
Understanding the molecular basis of cancer has increased dramatically in the last decade with the availability of the complete sequence of the human genome and the significant decrease in the cost of obtaining human DNA sequence information. This understanding has driven the desire for the development of “personalized medicine”, therapeutic agents tailored to the molecular defects found in an individual’s tumor. As a result, virtually all of the major pharmaceutical and biotech companies worldwide have identified oncology as an area of major interest for the development of new therapeutics.
The so-called liquid tumors, or tumors of the blood and lymphatic systems, including leukemia, lymphomas, and multiple myeloma, are cancer types where histone deacetylase (HDAC) inhibitors (HDACi) have shown clinical benefit and gained FDA approval. This collection of tumor indications represents roughly 10% of all cancer incidence and mortality.
HDACs act as one level of control on the pattern of gene expression in all types of human cells. Cancer cells have been shown to downregulate the expression level of proteins that interfere with their ability to survive and to upregulate the expression level of proteins that enhance their ability to survive. This regulation of gene expression has been linked in part to HDACs, hence the interest in HDACi as agents to potentially reverse these defense mechanisms.
More than 35 million people have died from AIDS, and there is no known cure for the disease despite over 30 different anti-HIV drugs approved for human use1. The current clinical strategy is to treat patients with a combination of commercial drugs that target different points in the viral life cycle. This antiretroviral therapy (ART) strategy was introduced in the 1990s and has resulted in a dramatic reduction in HIV-associated mortality and morbidity2. ART targets different points in the viral life cycle, including:
Latent pools of the virus are generally thought to be established in cells such as resting CD4+ memory T cells during the initial acute phase of HIV viral infection. These cell pools are resistant to ART and are transcriptionally silent until externally stimulated3. Transcriptional silencing in latent cell pools is maintained at the HIV long terminal repeat (LTR) promoter, where nucleosome-bound conformations prevent transcription and maintain the silent integrated viral DNA in a resting state. The latent resting pools represent an extremely stable reservoir with a half-life of 4 years or longer1.
There is mounting scientific evidence that histone deacetylases (HDACs) are actively involved in maintaining the transcriptionally silent cell pools. During the acute phase of HIV infection, the latent cell pools are maintained in a quiescent state or activated via complex interactions of the nucleosome, HIV regulatory proteins and eukaryotic transcription factors. The action of class 1 HDACs is required to maintain pro-viral quiescence, and studies have demonstrated that HDAC inhibition results in LTR activation and transcription of the latent pro-viral DNA1.
Several HDAC inhibitors (HDACi) have been evaluated for their ability to reactivate transcriptionally silent reservoirs in cells and HIV-infected patients2. These agents include vorinostat, givinostat, panobinostat, entinostat, mocetinostat, and romidepsin2. Use of first-line HDACi to activate latent viral pools may be hampered by toxicity issues associated with using these compounds at a clinically effective dose.
Together, these data demonstrate the validity of using HDACi to activate latent pro-viral HIV pools in HIV-infected patients. Cetya’s compounds exhibit enhanced class I specificity, best-in-class potency and reduced toxicity profiles that might be ideal candidates to use in combination with ART strategies to eradicate latent HIV viral pools and and potentially lead to a cure for HIV.
There is growing evidence that histone deacetylace (HDAC) inhibitors (HDACi) might be effective in treating certain neurodegenerative diseases. The current available treatments for Alzheimer’s, Parkinson’s, amyloid lateral sclerosis (ALS), and Huntington’s diseases do not cure the ailments but rather inhibit progression of the patient’s disease1. Scientific evidence continues to support the hypothesis that HDAC dysregulation plays a central role in the development and progression of neurodegenerative disorders and the resulting clinical pathologies.
Current evidence suggests that HDACi are potentially relevant clinical candidates to treat neurodegenerative diseases including Huntington’s2, Niemann-Pick Type C3-4 and Amyotrophic Lateral Sclerosis5.
© 2018 · Cetya Therapeutics