Dimeric HDAC Inhibitors
Summary Background: Nearly 10 million people throughout the world are diagnosed with cancer each year. The direct and indirect medical costs to treat cancer total more than $180 billion each year, and in the United States alone, cancer takes the lives of 1,500 people on average each day. One key target of recent cancer therapy approaches involves HDAC inhibitors, with over 15 different clinical trials currently ongoing. The exponential growth in the level of research activity surrounding the histone deacetylases (HDACs) witnessed over the past decade has, in part, been driven by the ability of HDAC inhibitors to modulate transcriptional activity. In tissue culture studies, this therapeutic class is able to block angiogenesis, cell cycle, and promote apoptosis and differentiation. HDAC inhibitors function by binding to the enzyme's active site and inhibiting the site-specific deacetylation of lysine residues on target substrates.A major drawback with the use of HDAC inhibitors in clinical trials is their toxicity. HDAC inhibitors target specific classes of HDACs (HDACs consist of three classes and a total of at least eighteen isoforms) rather than individual members, which is believed to contribute to side effects. A case in point is Curagen's lead HDAC inhibitor PXD101 for the treatment of multiple myeloma and T-cell lymphoma. In a phase I clinical trial the most common side-effects reported were fatigue, nausea, and vomiting as well as acute decrease in renal function. In another example, a phase II clinical trial of Gloucester Pharmaceuticals HDAC inhibitor depsipeptide for treatment of metastatic neuroendocrine tumors revealed severe cardiotoxicity. The promise of more effective treatments with HDAC inhibitors lies in the discovery of agents that can target isoform specific HDAC's. This would lead to reduced toxicity and greater efficacy in the treatment of cancer.
Invention: Harvard researchers have created a brand new class of HDAC inhibitors, so-called dimeric HDAC inhibitors. Dimeric HDAC inhibitors take advantage of the fact one HDAC isoform (HDAC 6) has two catalytic domains, each spaced a unique distance from each other. Additionally, other HDAC proteins are believed to function as pairs, or dimers, suggesting a plausible method for targeting other HDAC isoforms. The small molecule inhibitors are composed of two functional groups known to inhibit histone deacetylases spaced via a linker moiety. The precise distance separating the two functional groups allows for simultaneous binding in the pockets of the two HDAC active sites. The inhibitory functional groups of the small molecules may be two of the same inhibitory functional groups linked together, or they may be comprised of two different functional groups linked together.
Applications Representative Example: Dimeric WT-BH37 Inhibits HDAC 6 Function With Low- Digit Nanomolar Concentration EC50's: Recent evidence by the Schreiber laboratory suggests that deacetylation of microtubules by HDAC 6 is instrumental for a tumor's ability to migrate and, thus, metastasize. Given this link and other connections to cancer protein degradation it is important to find compounds capable of specifically inhibiting HDAC 6 for cancer treatment. The HDAC deacetylase and tubulin deacetylase (TDAC) inhibitory activities of control (WT-BM2), dimeric HDAC (WT-BAII), and monomeric HDAC compounds (WT-MH2) were measured (see below). WT-BAII was highly selective for tubulin (IC50 of 1.15 nm), whereas the monomeric counterpart WT-MH2 was not selective for tubulin (IC50 800 nm). Interestingly, WT-BH37 displayed only a slightly higher IC50 value (IC50 722 nm) against the HDAC substrate than that seen with its respective monomer WT-MH2 (IC50 567 nm). The control WT-BM2 showed no HDAC or TDAC inhibitory activity (IC50 >10 um). These results demonstrate that WT-BH37 is a potent (low-digit nanomolar concentrations) and highly selective inhibitor of tubulin deacetylation, a target of HDAC 6 activity, and a lead compound for the treatment for cancer.
Applications: Dimeric HDAC6 inhibitors are useful for the treatment of proliferative diseases, such as cancer, diabetic retinopathy, inflammatory diseases, angiogenesis, and infectious diseases. The lead compounds are also useful as tools to probe biological function (e.g., the dimerization of histone deacetylases).
Market: The market for anti-metastatic and anti-angiogeneic agents is large. There are over 21 million people living in the United States with cancer, with over 1 million newly diagnosed individuals each year. For Further Information Please Contact the Director of Business Development Laura Brass Email: [email protected] Telephone: (617) 495-3067
Inventor(s): Schreiber, Stuart L.
Type of Offer: Licensing
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