The Hedgehog (Hh) pathway has emerged as important therapeutic target in cancer, since its crucial role in tissues,development, proliferation and maintenance of cancer stem cells (CSCs) in tumors. The major issue in Hh-antagonist
development is due to drug-resistant Smo mutations and Gli1 hyperactivation.The clinical development of Smo antagonists has failed due to different issues including pharmacokinetics, low selectivity on CSCs or the emergence of drug resistance. Several evidences also suggest that cancer cells can acquire resistance to Smo antagonists by amplification/activation of Gli effectors or activation of external coordinated signals that bypass the Smo-mediated control. Therefore, the development of new compounds that could modulate Hh pathway has emerged as a better approach to cancer therapy. Due to structure-based approach and multidisciplinary efforts, we recently discovered the first small molecule, GlaB, able to impair Hh oncogenic activity by inhibiting Gli1/DNA interaction, providing a proof-of-principle for the therapeutic relevance of such an approach. We will investigate the translational potential of GlaB and we will test whether this strategy provide valuable insights for identifying, developing and optimizing new Smo and/or Gli-antagonists and promise a more effective treatment in Hh-dependent tumors and CSCs. The main goal of this proposal is the discovery of novel small molecules targeting Hh signaling at both upstream and downstream level to overcome anti-Smo resistance and affect Gli1/DNA interaction and its transcriptional function.A multidisciplinary research team will be established by mixing organometallic chemistry, plant natural compounds extracted by different matrices,plant natural compounds extracted by different matrices and computational studies, engineer and molecular biology expertise.Most promising compounds will be tested in vitro and in vivo for their efficacy to counteract the Hh-dependent tumors and CSCs growth.
