Macrocyclic inhibitors of upstream protein activators of the Hedgehog pathway

Hedgehog 通路上游蛋白激活剂的大环抑制剂

基本信息

批准号：
8895869
负责人：
Rudi Fasan
金额：
$ 20.03万
依托单位：
UNIVERSITY OF ROCHESTER
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：
2014-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8895869
关键词：
Affinity Antineoplastic Agents Binding Biological Assay Biological Factors Cancer Biology Carrier Proteins Cells Chemical Agents Chemicals Clinical Colon Carcinoma Combinatorial Synthesis Complex Cyclization DNA Development Embryonic Development Erinaceidae Evaluation Event Genes Genetic Genetic Transcription Goals Health Homologous Protein Human Hybrids In Vitro Inhibitory Concentration 50 Lead Libraries Ligands Link Macrocyclic Compounds Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Malignant neoplasm of prostate Mammalian Cell Mediating Methodology Minor Natural regeneration Outcome Pathway interactions Peptides Plasmids Play Process Property Proteins Recombinants Reporter Repression Research Role Signal Pathway Signal Transduction Signaling Protein Structure Surface Plasmon Resonance System Therapeutic Agents Validation Vertebral column Work adult stem cell analog anticancer research base cancer stem cell cancer therapy cross reactivity drug development human SMO protein inhibitor/antagonist innovation leukemia next generation patched protein protein aminoacid sequence protein complex protein protein interaction receptor scaffold screening small molecule smoothened signaling pathway stem cell biology stem cell division tool transcription factor tumor

项目摘要

DESCRIPTION (provided by applicant): The Hedgehog signaling pathway plays a key role during embryonic development and, post-embryonically, in regulating adult stem cell renewal and regeneration. Aberrant activation of the Hedgehog pathway has been linked to the development and progression of several human malignancies, including leukemia, lung, pancreatic, prostate, and colon cancers. Chemical modulators of the Hedgehog pathway have proven essential for elucidating its function as well as identifying promising clinical candidates for the treatment of Hedgehog pathway-related cancers. The majority of currently available Hedgehog pathway antagonists, however, target the transmembrane receptor Smoothened (Smo) and, to a minor extent, downstream pathway components involved in the activation of Gli transcription factors and transcription of Gli-regulated genes. In contrast, a fundamental gap remains with respect to chemical agents that can potently interfere with upstream events of Hedgehog pathway activation, namely the interaction between the Hedgehog signaling proteins and the Patched receptor, which is responsible for de-repression of Smo and consequent induction of Gli-regulated genes. The goal of this project is to develop a new class of macrocyclic organo-peptide inhibitors of the Hedgehog/Patched protein-protein interaction. To achieve this goal, we will utilize a modular and efficient strategy for creating vast and highly diverse libraries of functionally complex macrocycles in combination with a powerful, high-throughput system for functional screening of these libraries. The Hedgehog-targeting macrocycles isolated in this manner will be evaluated in secondary in vitro and cell-based assays in order to characterize their inhibitory potency, selectivity, and ability to block Hedgeho pathway signaling in mammalian cells. Ultimately, this research is expected to provide highly needed chemical probes for investigating the Hedgehog signaling pathway in stem cell biology and cancer biology, as well as new lead structures, readily amenable to further optimization, for the development of next-generation anticancer agents. Another relevant contribution of this project will be the implementation of a general, integrated platform for evolving macrocyclic inhibitors of protein complexes, which could be readily applied to a variety of other cancer-related target protein-protein interactions.

描述（由申请人提供）：Hedgehog 信号通路在胚胎发育过程中以及胚胎后调节成体干细胞更新和再生过程中发挥着关键作用。 Hedgehog 通路的异常激活与多种人类恶性肿瘤的发生和进展有关，包括白血病、肺癌、胰腺癌、前列腺癌和结肠癌。 Hedgehog 通路的化学调节剂已被证明对于阐明其功能以及确定治疗 Hedgehog 通路相关癌症的有前景的临床候选药物至关重要。然而，大多数目前可用的 Hedgehog 通路拮抗剂都靶向跨膜受体 Smoothened (Smo)，并在较小程度上靶向参与 Gli 转录因子激活和 Gli 调节基因转录的下游通路成分。相比之下，在能够有效干扰 Hedgehog 通路激活上游事件的化学试剂方面仍然存在根本差距，即 Hedgehog 信号蛋白和 Patched 受体之间的相互作用，后者负责 Smo 的去抑制并随后诱导Gli 调控基因。该项目的目标是开发一类新的 Hedgehog/Patched 蛋白-蛋白相互作用的大环有机肽抑制剂。为了实现这一目标，我们将利用模块化和高效的策略来创建庞大且高度多样化的功能复杂大环化合物库，并结合强大的高通量系统对这些库进行功能筛选。以这种方式分离的 Hedgehog 靶向大环化合物将在二次体外和基于细胞的测定中进行评估，以表征其抑制效力、选择性以及阻断哺乳动物细胞中 Hedgeho 途径信号传导的能力。最终，这项研究预计将为研究干细胞生物学和癌症生物学中的 Hedgehog 信号通路提供急需的化学探针，以及易于进一步优化的新先导结构，用于开发下一代抗癌药物。该项目的另一个相关贡献是实施一个通用的、集成的平台，用于进化蛋白质复合物的大环抑制剂，该平台可以很容易地应用于各种其他与癌症相关的靶蛋白-蛋白质相互作用。