title: Scaffold hopping approach to a new series of smoothened antagonists.
abstract: The hedgehog (Hh) signaling pathway is a key regulator during embryonic development, while in adults, it has limited functions such as stem cell maintenance and tissue repair. The aberrant activity of the Hh signaling in adults has been linked to numerous human cancers. Inhibition of Hh signaling therefore represents a promising approach toward novel anticancer therapies. The Smoothened (Smo) receptor mediates Hh signaling. Here we report a new series of Smo antagonists which were obtained by a scaffold hopping strategy. Compounds from this new scaffold demonstrated decent inhibition of Hh pathway signaling. The new scaffold can serve as a starting point for further optimization.
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Su Zhou, Jiangsu 215021, PR China.
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Lu
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Su Zhou, Jiangsu 215021, PR China.
authors.forename: Delong
authors.initials: D
authors.lastname: Geng
authors.affiliation: BeiGene (Beijing) Co., Ltd, No. 30 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, PR China.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Su Zhou, Jiangsu 215021, PR China.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Su Zhou, Jiangsu 215021, PR China.
authors.forename: Haikuo
authors.initials: H
authors.lastname: Ma
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Su Zhou, Jiangsu 215021, PR China.
authors.forename: Jiyue
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Su Zhou, Jiangsu 215021, PR China. Electronic address: xiaohuzhang@suda.edu.cn.
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D000072086:Smoothened Receptor
chemical_list: D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor
keywords: Antagonist; Cancer therapy; GPCR; Hedgehog pathway; Scaffold hopping; Smoothened