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（由适用提供）：不受控制的GLI转录因子活性会导致几种人类癌症，包括碱性细胞癌，髓母细胞瘤，脑膜瘤和横纹肌肉瘤。刺猬（HH）途径失调的致癌GLI功能经常功能，并且该发育中的信号传导途径的化学抑制剂现在正在临床使用中。尽管我们在理解和治疗GLI依赖性癌症方面取得了重大进展，但当前涉及HH途径靶向疗法仍有几个局限性。首先，几乎所有靶向HH途径的药物都抑制了平滑（SMO），这是HH信号转导所需的G蛋白偶联受体样蛋白。结果，它们主要是有效的针对由Patched1（PTCH1），SMO的跨膜反射器或SMO中某些激活突变引起的癌症。由下游或平行信号机制引发的GLI依赖性肿瘤对这些化合物不敏感。其次，由于药物抗药性细胞可以快速出现，因此SMO拮抗剂引起的肿瘤回归通常是短暂的。第三，靶向SMO靶向药物会破坏正常的HH途径依赖性生理学，而临床前研究进一步表明SMO封锁可能会导致儿童发育缺陷。 HH途径抑制剂在SMO下游和更直接抑制GLI功能的抑制剂可以克服这些约束。特别是，选择性抑制GLI1的化合物可能是更一般和有效的抗癌剂，因为该GLI同工型是一种潜在的癌基因，但对于哺乳动物的发育和生理学来说是可用的。为了实现这一目标，我们的实验室最近对325,120种化合物进行了调查，以抑制缺乏直接GLI拮抗剂Fususe（Sufu）抑制器的细胞中的本构GLI活性。通过这个大型化学筛选，我们已经确定了可以抑制GLI1功能但对GLI2或GLI3没有明显影响的咪唑衍生物（“ Glimidazole”）。我们还开发了几种在基于细胞的测定中具有纳摩尔电位的Glimidazole类似物，使用了光性标记，以发现特定的Glimidazole结合蛋白，该蛋白可能会将线粒体信号传导和GLI1调节联系起来，并证明了这些GLI1 - 选择性抑制剂的能力，以阻止肿瘤在体外的肿瘤生长。现在，我们正在追求建立基于Glimidazole的化合物作为新的HH途径靶向化学疗法所需的下一步。我们的目标是：（1）表征我们的光性标记实验中发现的glimidazole靶标，并确定其在Gli1调节中的作用；（2）开发具有优化效力，目标选择性和药代动力学特性的Glimidazole类似物；（3）将选定的Glimidazole级分子与髓母细胞瘤模型中SMO拮抗剂的效率进行比较。综上所述，我们的研究将提供有关GLI1调节机制，发现抗癌疗法的新靶标，并为未来的药物开发工作产生化学铅的新见解。