Purushottamachar Puranik - First Chemical Feature Based Pharmacophore Modeling of Potent Retinoidal Retinoic Acid Metabolism Blocking Agents (RAMBAs): Identification of Novel RAMBA Scaffolds

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      Publication Details (including relevant citation   information):

      In Press: doi:10.1016/j.ejmech.2011.11.010



      The naturally occurring retinoids and their synthetic analogs   play a key role in differentiation, proliferation, and apoptosis,   and their use/potential in oncology, dermatology and a variety of   diseases are well documented. This review focuses on the role of   all-trans-retinoic acid   (ATRA), the principal endogenous metabolite of vitamin A   (retinol) and its metabolism in oncology and dermatology. ATRA   has been used successfully in differentiated therapy of acute   promyelocytic leukemia, skin cancer, Kaposi’s sarcoma, and   cutaneous T-cell lymphoma, and also in the treatment of acne and   psoriasis. However, its usefulness is limited by the rapid   emergence of acquired ATRA resistance involving multifactoral   mechanisms. A key mechanism of resistance involves ATRA-induced   catabolism of ATRA. Thus, a novel strategy to overcome the   limitation associated with exogenous ATRA therapy has been to   modulate and/or increase the levels of endogenous ATRA by   inhibiting the cytochrome P450-dependent ATRA-4-hydroxylase   enzymes (particularly CYP26s) responsible for ATRA metabolism.   These inhibitors are also referred to as retinoic acid metabolism   blocking agents (RAMBAs). This review highlights development in   the design, synthesis, and evaluation of RAMBAs. Major emphasis   is given to liarozole, the most studied and only RAMBA in   clinical use and also the new RAMBAs in development and with   clinical potential.

      Address (URL): http://www.sciencedirect.com/science/article/pii/S0223523411008300