Ingenol Disoxate: A Novel 4-Isoxazolecarboxylate Ester of Ingenol with Improved Properties for Treatment of Actinic Keratosis and Other Non-Melanoma Skin Cancers

• DOI: 10.1007/s13555-016-0137-2
• Publication Date: 2016-08-08T11:47:15Z
• Authors: Malene Bertelsen; Martin Stahlhut; Gunnar Grue-Sørensen; Xifu Liang; Gitte Bach Christ...; Kresten Skak; Karen Margrethe E...; Thomas Högberg
• Keywords: Actinic keratosis

Ingenol mebutate gel (Picato®, LEO Pharma A/S) is approved for the field treatment of actinic keratosis and characterized by high sustained clearance lesions. The inherent propensity ingenol towards chemical rearrangement necessitates refrigeration final product. We sought to identify novel derivatives with enhanced stability similar or improved in vitro potency vivo efficacy. A number esters were synthesized full regiocontrol from ingenol. Chemical was determined aqueous buffer at physiological pH hydroalcoholic lower pH. Acute cytotoxicity HeLa HSC-5 cells. Keratinocyte proliferation, viability caspase 3/7 activation measured primary epidermal keratinocytes. Relative gene expression levels real-time quantitative PCR. Evaluation tumor ablating potential performed murine B16 melanoma mouse model UV-induced skin carcinogenesis hairless SKH-1 mice following topical two consecutive days test compounds formulated 0.1% a gel. This work resulted identification disoxate (LEO 43204) displaying increased clinically relevant formulation minimal pH-dependent acyl migration degradation. exhibited significantly higher cytotoxic relative mebutate. Likewise, cell growth arrest normal human keratinocyte more potently induced disoxate, which accompanied protein kinase C dependent transcription markers differentiation. Most notably, possessed superior antitumor effect median survival time significant on ablation also observed ultraviolet irradiation-induced carcinogenesis. These data illustrate that favorable pharmacological properties driving efficacy are either preserved disoxate. In combination potentially facilitate storage product ambient temperatures, these features support further development as convenient efficacious modality non-melanoma cancers. A/S.