Design and Characterization of a Novel, Reverse Prodrug Histone Deacetylase Inhibitor for Cutaneous T-Cell Lymphoma. (2006)

Abstract Cutaneous T-Cell Lymphoma (CTCL) comprises a group of related lymphoproliferative disorders characterized by the presence of malignant lymphocytes in the skin. The most common variant is Mycosis Fungoides (MF), which affects approximately 500 patients per year in the United States. Though most patients with MF enjoy a normal life expectancy, they experience chronic morbidity due to the symptomatic and cosmetic manifestations of epidermotropism: erythematous patches, elevated plaques, alopecia, and cellulitis. Many patients will experience progressive disease with lymph node infiltration, tumor and a leukemic phase termed the Sezary Syndrome. The lack of a survival benefit offered by clinical trials of combination chemotherapy and radiation supports the current standard of initial topical therapy for most patients with CTCL. Topical or skin-directed approaches widely offered include: nitrogen mustards (meclorethamine or carmustine), corticosteroids, oral psoralen with UVA radiation, UVB phototherapy and electron beam irradiation. Recent, early phase clinical studies of histone deacetylase inhibitors (HDACi) have illustrated a remarkable activity among patients with advanced CTCL. The structural dissimilarity of these ligands supports an on-target antineoplastic effect. Unfortunately, the frequently severe side effects associated with the systemic delivery of these nonselective ligands may limit their downstream clinical utility in the majority of patients with this disease, even with topical administration. We therefore devised a chemical strategy to achieve high dose-intensity at the site of cutaneous disease following topical administration with limited systemic exposure. Suberohydroxamic acid phenyl ester (SHAPE) is a first-in-class reverse prodrug inhibitor of histone deacetylases. Between the aliphatic chain and aromatic capping element of this canonical HDACi, we positioned an ester bond so as to promote presystemic metabolism by serum esterases. Preclinical studies of this ligand demonstrate potent activity against nuclear and cytosolic HDAC proteins. Doses required to achieve maximal histone hyperacetylation in human cancer cell tissue culture are comparable to vorinostat (SAHA; Merck &amp; Co., Rahway, NJ) and MS-275 (Berlex Pharmaceuticals, Montville, NJ). These studies support the stability of SHAPE in the intracellular environment amid cellular esterases. The rapid metabolism (t-½ less than 5 minutes) by serum esterases has been established biochemically using continuous spectrophotometry, and is mediated by both butyrylcholinesterase and paraoxonase. Tolerability and preliminary activity have recently been demonstrated in an IL-7 transgenic mouse model of CTCL supporting clinical development as a therapeutic strategy in humans. Application to premalignant, neoplastic and inflammatory conditions of the oropharynx is being explored. Further studies characterizing the impact of SHAPE on T-cell function are also ongoing, to assess utility in conditions such as psoriasis and cutaneous graft-versus-host disease.