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

• 批准号: 8755152
• 负责人: Rudi Fasan
• 金额: $ 16.69万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 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/8755152
• 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; 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; public health relevance; receptor; scaffold; screening; small molecule; smoothened signaling pathway; stem cell biology; stem cell division; tool; transcription factor; tumor

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发育后在调节成体干细胞更新和再生中起关键作用。Hedgehog通路的异常激活与几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鉴定用于治疗Hedgehog通路相关癌症的有前景的临床候选物至关重要。然而，大多数目前可用的Hedgehog途径拮抗剂靶向跨膜受体Smoothened（Smo），并且在较小程度上靶向参与Gli转录因子活化和Gli调节基因转录的下游途径组分。相比之下，一个基本的差距仍然相对于化学试剂，可以有力地干扰上游事件的刺猬途径激活，即刺猬信号蛋白和补丁受体之间的相互作用，这是负责去抑制Smo和随后的诱导GLI调节的基因。本项目的目标是开发一类新的Hedgehog/Patched蛋白质-蛋白质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功能复杂的大环化合物的巨大和高度多样化的库，并结合功能强大的高通量系统来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级体外和基于细胞的测定中进行评价，以表征其抑制效力、选择性和阻断哺乳动物细胞中Hedgeho途径信号传导的能力。最终，这项研究预计将提供高度需要的化学探针，用于研究干细胞生物学和癌症生物学中的Hedgehog信号通路，以及新的先导结构，易于进一步优化，用于开发下一代抗癌药物。该项目的另一个相关贡献将是实施一个通用的综合平台，用于开发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癌症相关的靶蛋白-蛋白质相互作用。