Development of Gli1-Selective Therapeutics for Hedgehog Pathway-Dependent Cancers

Hedgehog 通路依赖性癌症的 Gli1 选择性疗法的开发

基本信息

批准号：
8648531
负责人：
Alison Evelynn Ondrus
金额：
$ 5.7万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8648531
关键词：
Address Adolescent Adult Affect Allografting Automobile Driving Basal cell carcinoma Base Sequence Binding Binding Proteins Biochemical Biochemical Genetics Biological Brain Cancer Etiology Cancer Model Cells Child Childhood Childhood Medulloblastomas Clinical Collaborations Defect Development Disease Drug Kinetics Embryo Embryonic Development Epigenetic Process Erinaceidae Event FDA approved G Protein-Coupled Receptor Genes G-Protein-Coupled Receptors Gene Expression Gene Expression Profile Gene Targeting Genetic Growth and Development function Human Lead Left Length Ligand Binding Malignant Childhood Neoplasm Malignant Neoplasms Mass Spectrum Analysis Mediating Minor Modeling Modification Mus Mutation N-terminal Oncogenic Pancreatic Adenocarcinoma Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Phosphorylation Property Proteins Proteolytic Processing Regulation Resistance Role Scaffolding Protein Signal Transduction Skeleton Skin Spinal Cord Structure Structure-Activity Relationship Therapeutic Time Tissues Transcription Coactivator analog cellular targeting chemical synthesis clinical application gain of function human SMO protein inhibitor/antagonist lung small cell carcinoma meningioma next generation polypeptide postnatal prevent public health relevance receptor research study skeletal small molecule smoothened signaling pathway success therapeutic target transcription factor tumor tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Hedgehog (Hh) signaling coordinates events in embryogenesis but is largely quiescent in differentiated tissue. Uncontrolled activation of the pathway is implicated in a variety of human cancers, including pediatric medulloblastoma and essentially all basal cell carcinomas. Its causative role in oncogenesis highlights this pathway as a therapeutic target, and the first FDA-approved Hh antagonist (vismodegib) has shown remarkable tumor inhibition in advanced basal cell carcinomas. Despite its initial success, cases of vismodegib resistance have begun to emerge, and developmental defects in mice caused by analogs raises concerns about its use in children. Next-generation therapies are necessary to overcome these limitations and fully realize the clinical potential of Hh pathway inhibition. Normal signaling is stimulated when the Hh ligand binds to the receptor Patched (Ptc), which releases inhibition of the GPCR-like protein Smoothened (Smo). Smo inhibits the negative pathway regulator Suppressor of Fused (Sufu) and effects activation of the Gli transcription factors (Gli1, Gli2, and Gli3) that mediate pathway activity. Since vismodegib and nearly all small molecule Hh inhibitors antagonize Smo, cancers initiated downstream of Smo are insensitive to these compounds. Smo is also particularly susceptible to mutations that confer resistance after sustained treatment. To find a pathway antagonist that circumvents these limitations, the Chen lab recently completed a screen of 325,120 compounds for their ability to inhibit pathway activity induced by loss of Sufu. These studies identified an imidazolium compound, henceforth termed glimidazole, that selectively blocks Gli1 activity but leaves Gli2 and Gli3 intact. Due to its direct inhibition of the Gli1, glimidazole compounds have potential as a broad-spectrum treatments for Hh-dependent cancers. Furthermore, while Gli2 and Gl3 are essential for development, Gli1-/- mice show no obvious defects, suggesting that Gli1-selective antagonists may provide a therapy for childhood patients. To develop the clinical potential of glimidazole derivatives, we will (1) identify and functionally characterize the cellular target of glimidazole, and (2) assess the effects of glimidazole analogs on tumorigenesis and murine development. We will synthesize glimidazole derivatives to enable the isolation of specific binding proteins and characterize interactors by mass spectrometry-based sequencing. Concurrently, we will use whole-transcriptome comparisons of glimidazole-sensitive and glimidazole-resistant cells to identify potential glimidazole targets. To discern the physiologicaly relevant glimidazole target from other interacting proteins, we will assess their roles in Hh pathway regulation through loss- and gain-of-function perturbations. We will exploit a modular chemical synthesis of glimidazole structures to optimize their potency, selectivity, and pharmacokinetic properties through medicinal chemistry. In collaboration with Prof. Jean Tang, we will evaluate the most promising analogs in a basal cell carcinoma allograft model, and compounds that inhibit tumor progression will be evaluated in juvenile mice for teratogenic effects.

描述（由申请人提供）：Hedgehog (Hh) 信号传导协调胚胎发生中的事件，但在分化组织中大部分处于静止状态。该通路的不受控制的激活与多种人类癌症有关，包括儿科髓母细胞瘤和基本上所有基底细胞癌。它在肿瘤发生中的致病作用凸显了该途径：作为治疗靶点，FDA 批准的第一个 Hh 拮抗剂 (vismodegib) 在晚期基底细胞癌中显示出显着的肿瘤抑制作用。尽管取得了初步成功，但 vismodegib 耐药病例已经开始出现，并且由类似物引起的小鼠发育缺陷引起了对其在儿童中使用的担忧。下一代疗法必须克服这些限制并充分发挥 Hh 通路抑制的临床潜力。当 Hh 配体与受体 Patched (Ptc) 结合时，会刺激正常信号传导，从而释放对 GPCR 样蛋白 Smoothened (Smo) 的抑制。 Smo 抑制负通路调节因子 Fused Suppressor (Sufu)，并影响介导通路活性的 Gli 转录因子（Gli1、Gli2 和 Gli3）的激活。由于 vismodegib 和几乎所有小分子 Hh 抑制剂都会拮抗 Smo，因此 Smo 下游引发的癌症对这些化合物不敏感。 Smo还特别容易受到持续治疗后产生耐药性的突变的影响。为了找到一种绕过这些限制的途径拮抗剂，Chen 实验室最近完成了对 325,120 种化合物的筛选，以确定它们抑制由 Sufu 丢失引起的途径活性的能力。这些研究发现了一种咪唑鎓化合物（以下称为格列咪唑），它可以选择性地阻断 Gli1 活性，但使 Gli2 和 Gli3 保持完整。由于其直接抑制 Gli1，格列咪唑化合物具有作为 Hh 依赖性癌症的广谱治疗的潜力。此外，虽然 Gli2 和 Gl3 对于发育至关重要，但 Gli1-/- 小鼠没有表现出明显的缺陷，这表明 Gli1 选择性拮抗剂可能为儿童患者提供治疗。为了开发格列咪唑衍生物的临床潜力，我们将（1）鉴定格列咪唑的细胞靶点并对其进行功能表征，以及（2）评估格列咪唑类似物对肿瘤发生和小鼠发育的影响。我们将合成格列咪唑衍生物，以分离特异性结合蛋白，并通过基于质谱的测序来表征相互作用物。同时，我们将使用格列咪唑敏感和格列咪唑耐药细胞的全转录组比较来识别潜在的格列咪唑靶标。为了区分生理相关的格列咪唑靶点和其他相互作用的蛋白质，我们将通过功能丧失和功能获得扰动评估它们在 Hh 通路调节中的作用。我们将利用格列咪唑结构的模块化化学合成，通过药物化学优化其效力、选择性和药代动力学特性。我们将与 Jean Tang 教授合作，在基底细胞癌同种异体移植模型中评估最有前途的类似物，并在幼年小鼠中评估抑制肿瘤进展的化合物的致畸作用。