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Gli1-selective inhibitors of the Hedgehog signaling pathway

Hedgehog 信号通路的 Gli1 选择性抑制剂

基本信息

批准号：
9100825
负责人：
JAMES K CHEN
金额：
$ 35.07万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9100825
关键词：
Adolescent Adult Allografting Altered Taste Antineoplastic Agents Basal cell carcinoma Binding Binding Proteins Biochemical Biological Assay Cancer Etiology Cell model Cell physiology Cells Chemicals Child Clinical Clinical Research Defect Development Drug Kinetics Drug Targeting Drug resistance Embryonic Development Erinaceidae Esthesia Family Fostering Future G-Protein-Coupled Receptors Genetic Genetic Transcription Goals Growth Hair Health Human Imidazole In Vitro Integral Membrane Protein Investigation Laboratories Lead Link Malignant Neoplasms Mitochondria Mitogen-Activated Protein Kinases Modeling Mus Muscular Atrophy Mutation Names Oncogenes Oncogenic Pathway interactions Patients Pharmaceutical Preparations Phosphatidylinositols Phosphotransferases Photoaffinity Labels Physiology Predisposition Property Protein Isoforms Proteins Proteomics Regulation Resistance Rhabdomyosarcoma Role Signal Pathway Signal Transduction Site Structure-Activity Relationship Surveys TP53 gene Tissues United States Food and Drug Administration Up-Regulation analog base cancer cell cancer therapy chemical synthesis chemotherapy comparative efficacy drug development experience fusion gene hedgehog signal transduction human disease improved in vivo inhibitor/antagonist insight medulloblastoma meningioma mouse model nanomolar next generation novel pharmacophore preclinical study prevent research study resistance mechanism skeletal small molecule smoothened signaling pathway stem targeted treatment therapeutic target transcription factor tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Uncontrolled Gli transcription factor activity causes several human cancers, including basal cell carcinoma, medulloblastoma, meningioma, and rhabdomyosarcoma. Oncogenic Gli function frequently stems from Hedgehog (Hh) pathway dysregulation, and chemical inhibitors of this developmental signaling pathway are now in clinical use. Despite these significant advances in our understanding and treatment of Gli- dependent cancers, current Hh pathway-targeting therapies have several limitations. First, nearly all Hh pathway-targeting drugs inhibit Smoothened (Smo), a G protein-coupled receptor-like protein that is required for Hh signal transduction. As a result, they are primarily effective against cancers caused by loss of Patched1 (Ptch1), a transmembrane repressor of Smo, or by certain activating mutations in Smo. Gli-dependent tumors initiated by downstream or parallel signaling mechanisms are insensitive to these compounds. Second, tumor regressions induced by Smo antagonists are often transient, as drug-resistant cancer cells can rapidly emerge. Third, Smo-targeting drugs can disrupt normal Hh pathway-dependent physiology, and preclinical studies further suggest that Smo blockade could cause developmental defects in children. Hh pathway inhibitors that act downstream of Smo and more directly suppress Gli function could overcome these constraints. In particular, compounds that selectivity inhibit Gli1 could be more general and effective anti-cancer agents, since this Gli isoform is a potent oncogene but dispensable for mammalian development and physiology. Toward this goal, our laboratory recently surveyed 325,120 compounds for their ability to inhibit the constitutive Gli activity in cells lacking Suppressor of Fused (Sufu), a direct Gli antagonist. Through this large-scale chemical screen, we have identified an imidazole derivative ("glimidazole") that can inhibit Gli1 function but has no apparent effect on Gli2 or Gli3. We have also developed several glimidazole analogs with nanomolar potencies in cell-based assays, used photoaffinity labeling to discover a specific glimidazole-binding protein that may link mitochondrial signaling and Gli1 regulation, and demonstrated the ability of these Gli1-selective inhibitors to block tumor growth in vitro and in vivo. We are now pursuing the next steps required to establish glimidazole-based compounds as a new class of Hh pathway-targeting chemotherapies. Our aims are: (1) to characterize the glimidazole target discovered in our photoaffinity labeling experiments and determine its roles in Gli1 regulation; (2) to develop glimidazole analogs with optimized potency, target selectivity, and pharmacokinetic properties; and (3) to compare the efficacy of selected glimidazole-class molecules to Smo antagonists in murine models of medulloblastoma. Taken together, our studies will provide new insights into the mechanisms of Gli1 regulation, uncover novel targets for anti-cancer therapies, and yield chemical leads for future drug development efforts.