Hedgehog(Hh)信号通路对众多肿瘤的发生和发展起着重要作用。靶向其受体Smoothened（Smo）的抗肿瘤药物已经成功上市，但其原发性及继发性耐药严重影响了其临床疗效。研究发现靶向Hh信号通路下游转录因子Gli是克服Smo抑制剂原发及继发性耐药的理想策略。具有新型结构的小分子抑制剂SOMCL-15-631是本实验室和上海药物所张翱课题组联合研发的具有自主知识产权的高效Hh抑制剂，前期工作基础提示其作用靶点或为转录因子Gli。本项目拟在我们前期工作基础上全面、深入阐明SOMCL-15-631分子作用靶点、明确其对Smo抑制剂原发性、继发性耐药的克服作用。本项目的工作将为进一步开发SOMCL-15-631为具有自主知识产权的抗肿瘤药物提供前期试验依据，并且或能发现新的可用于开发靶向Hh信号通路抗肿瘤药物的崭新靶点，因此具有重要的学术及应用价值。

A wide range of tumors are driven by the Hedgehog (Hh) signaling pathway. Small molecular inhibitors targeting its critical component, Smoothened (Smo), have been approved for clinical treatment of advanced basal cellular carcinoma. Howerer, the primarily and acquired resistance to current Smo inhibitors heavily limited its clinical efficacy. Emerging evidences suggest small molecular inhibitors targeting at the level of Gli represents a good strategy to combat the primarily and acquired resistance to current Smo inhibitors. SOMCL-15-1631 is a Hh inhibitors with novel chemical structure developed by our lab and Ao Zhang's lab from Shanghai Institute of Materia Medica. Our data indicate that SOMCL-15-631 possibily inhibits the Hh signaling pathway at the level of Gli. Based on our obtained data, this proposal is aimed to futher deeply elucidate critical issues of SOMCL-15-631: 1). to fuerther demonstrate that SOMCL-15-631 is a Gli inhibitor; 2). to define the molecular target of SOMCL-15-631; 3). to investigate whether SOMCL-15-631 may combat the primarily and acquired resistance to current Smo inhibitors in vitro and in vivo. These studies will provide fundamental data for further developing SOMCL-15-631; meanwhile, the mechanisms studies defining the molecular target of SOMCL-15-631 in this proposal will possibly present a novel target for developing Hh inhibitors with ability of combating the primarily and acquired resistance to currrent Smo inhibitors.