Ricerc@Sapienza

The Hedgehog (Hh) pathway has emerged as a new target in cancer treatment, since it is hyperactivated in cancer stem cells (CSCs) in several tumors. The major issues in Hh-antagonist development are drug-resistant Smo mutations and Gli1 hyperactivation. The clinical development of Smo antagonists has often failed because of different issues including pharmacokinetics, low selectivity on CSCs or drug resistance. The development of new modulators of Hh pathway has emerged as a more promising approach to cancer therapy. The in silico screening of an in house library toward the Smo and Gli1 proteins identified several potential Hh-inhibitors, among which, glabrescione B and vismione E showed the best activity in vitro tests, but we focused on the former, since the latter displayed chemical instability. The objective of this proposal is the development and optimization of new Smo and/or Gli-antagonists by the rational structure-based design and synthesis of several derivatives of the two lead compounds. A multidisciplinary research team which owns expertise in organic synthesis, computational chemistry, molecular and structural biology, will identify new Hh-modulators by a computational approach: these compounds will be later synthetized mainly through organometallic catalysis, and then evaluated in vitro. The discovery and development of new green, atom-economic or high efficient chemical reactions is a priority, in order to optimize the synthetic process and minimize the wastes. Potency, specificity and pharmaceutical properties of selected candidates will be optimized by computational design, organic chemistry and biopharmaceutical studies. Most promising compounds will be tested in vitro and in vivo for their efficacy against the Hh-dependent tumors. The subsequent step will be the development of new formulation platforms that are suitable for permitting the drug delivery to the brain, a crucial issue in the administration of drugs for the treatment of brain tumors.