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.

描述（由申请人提供）：不受控制的 Gli 转录因子活性会导致多种人类癌症，包括基底细胞癌、髓母细胞瘤、脑膜瘤和横纹肌肉瘤。致癌性 Gli 功能通常源于 Hedgehog (Hh) 通路失调以及该发育信号通路的化学抑制剂。尽管我们对 Gli 依赖性癌症的理解和治疗取得了这些重大进展，但目前的 Hh 通路靶向疗法仍存在一些局限性。首先，几乎所有 Hh 通路靶向药物都会抑制 Smoothened (Smo)，这是一种 Hh 信号转导所需的 G 蛋白偶联受体样蛋白，因此它们主要有效。对抗因 Patched1 (Ptch1)（Smo 的跨膜抑制因子）缺失或由下游或平行信号传导机制引发的 Smo 某些激活突变引起的癌症。其次，Smo 拮抗剂诱导的肿瘤消退不敏感。第三，Smo 靶向药物可以破坏正常的 Hh 通路依赖性生理机能，临床前研究进一步表明 Smo 阻断可能是短暂的。作用于 Smo 下游并更直接抑制 Gli 功能的 Hh 通路抑制剂可以克服这些限制。特别是，选择性抑制 Gli1 的化合物可能是更通用和有效的抗癌药物，因为这种 Gli 亚型是一种。强效致癌基因，但对于哺乳动物的发育和生理学而言是可有可无的。为了实现这一目标，我们的实验室最近调查了 325,120 种化合物在缺乏 Gli 抑制剂的细胞中抑制组成型 Gli 活性的能力。 Fused (Sufu)，一种直接的Gli拮抗剂。通过这种大规模的化学筛选，我们已经鉴定出一种咪唑衍生物（“格列咪唑”），它可以抑制Gli1功能，但对Gli2或Gli3没有明显影响。我们还开发了几种格列咪唑。在基于细胞的测定中具有纳摩尔效力的类似物，使用光亲和标记发现了一种特定的格列咪唑结合蛋白，该蛋白可能将线粒体信号传导和 Gli1 调节联系起来，并证明了这种能力我们现在正在采取下一步行动，将基于格列咪唑的化合物建立为一类新型 Hh 通路靶向化疗药物。在我们的光亲和标记实验中发现的格列咪唑靶标，并确定其在 Gli1 调节中的作用；(2) 开发具有优化效力、靶标选择性和药代动力学特性的格列咪唑类似物； (3) 比较选定的格列咪唑类分子与 Smo 拮抗剂在髓母细胞瘤小鼠模型中的功效总而言之，我们的研究将为 Gli1 调节机制提供新的见解，揭示抗癌治疗的新靶点，并产生化学物质。为未来的药物开发工作提供指导。