Developing Chemical Probes for Oncogenic Signaling Pathways

开发致癌信号通路的化学探针

• 批准号: 10246934
• 负责人: Harshani R Lawrence
• 金额: $ 19.76万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-21 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246934
• 关键词: ACK1 Gene; Address; Advanced Development; Affinity; Antineoplastic Agents; Applications Grants; Automobile Driving; Award; Biology; Calendar; Cancer Center; Chemicals; Clinic; Collaborations; Communities; Development; Drug Targeting; Excipients; Formulation; Funding; Goals; Human; JAK2 gene; Libraries; Malignant Neoplasms; Mission; Molecular; Molecular Biology; Molecular Immunology; Molecular Medicine; Oncogenic; Peer Review; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phosphotransferases; Positioning Attribute; Principal Investigator; Prodrugs; Proteasome Inhibitor; Protein Tyrosine Kinase; Proteins; Proteomics; Public Health; Publications; Research; Research Design; Research Personnel; Research Project Grants; Signal Pathway; Signal Transduction; Sodium Chloride; Solvents; Specificity; Structure; Synthesis Chemistry; United States National Institutes of Health; Validation; base; cancer therapy; chemical synthesis; clinical development; design; drug candidate; drug discovery; in vivo; inhibitor/antagonist; kinase inhibitor; lead optimization; member; mutant; novel; novel strategies; novel therapeutics; patient population; programs; protein degradation; scale up; small molecule; success; targeted treatment

Abstract: The goal of this project titled “Developing chemical probes for oncogenic signaling pathways” is to promote identification of small molecules/chemical probes for cancer targets to elucidate underlying molecular mechanisms driving cancer and drug discovery efforts at the Moffitt Cancer Center (MCC). My Unit Director Dr. Said Sebti, is the Program Leader of the Chemical Biology Molecular Medicine (CBMM) program and Chair of the Drug Discovery Department, and recently awarded an R35 outstanding investigator award. I have demonstrated success in several medicinal chemistry projects in collaboration with Principal Investigators, and the 5 projects described in this application are funded via NCI. These projects will involve development of: 1. ACK1, 2. Mutant KRas, 3. Dual Aurora A /JAK2 inhibitors 4. Chemical probes to understand the mechanism of action of targeted drugs, and 5. Bifunctional molecules to target protein degradation. The synthetic chemistry strategies/approaches described in my proposal are expected to generate novel compounds to address significant challenges in several types of human cancers. The synthesis and validation of bifunctional molecules as PROTACs in kinase projects (ACK1, Aurora A-JAK2) is expected to advance the field/help to define tractable targets for this approach and provide new cancer therapies. As part of this award, I will continue to provide the Moffitt research community with critical enabling chemical biology support. This will include: structure based design and synthesis of focused libraries (hit-to-lead-optimization) to identify new compounds/chemical probes to explore the molecular mechanisms of proteins involved in cancer; scale-up synthesis and formulation of potent compounds (e.g. prodrug/salt formation, solvent/excipient optimization) for in-vivo studies; design/synthesis of chemical probes for affinity-based proteomics. In addition to the projects described here, I have several other medicinal chemistry collaborations with Cancer Center members that will lead to new directions in cancer therapy and I am in a unique position to integrate projects from the CBMM and Immunology programs. My contribution via synthesis of compounds was essential for peer reviewed publications and grant applications. Some of the major findings enabled by my contributions over the past 5 years include: (i) synthesis and development of Aurora A-JAK2 inhibitors and their application in GVHD; (ii) identification of novel, potent ACK1 inhibitors; (iii) synthesis of chemical probes for assessing target specificity of in-clinic tyrosine kinase and PARP inhibitors; (iv) synthesis/development of dual BRD4-kinase inhibitors, and (v) development of novel non- covalent proteasome inhibitors. I strongly believe the research projects described in this application will facilitate new directions, approaches, new chemical probes and drugs to study and target cancer, and I will devote 70% of my efforts (8.4 calendar months) to this award.

摘要：该项目的目的为“为致癌信号通路开发化学问题”的目的是 促进对癌症靶标的小分子/化学问题的鉴定以阐明基础 莫菲特癌症中心（MCC）推动癌症和药物发现工作的分子机制。我的 单位主管Sebti博士是化学生物学分子医学（CBMM）的计划负责人 计划和药物发现部门主席，最近授予了R35杰出 研究者奖。我在合作的几个药物化学项目中都取得了成功 与主要研究人员以及本申请中描述的5个项目是通过NCI资助的。这些 项目将涉及：1。ACK1，2。Mutant Kras，3。DualAurora A/JAK2抑制剂4。 了解靶向药物作用机理的化学问题，5。双功能分子至 靶蛋白降解。我的提案中描述的合成化学策略/方法是 预计将产生新颖的化合物，以应对几种人类的重大挑战 癌症。双功能分子在激酶项目中的合成和验证（ACK1， 预计Aurora a-jak2）将推进领域/帮助以定义此方法的可拖动目标并提供 新的癌症疗法。作为该奖项的一部分，我将继续为莫菲特研究社区提供 至关重要的化学生物学支持。这将包括：基于结构的设计和聚焦的合成 库（命中率优化）以识别新化合物/化学问题以探索分子 参与癌症的蛋白质机制；扩大合成和制定潜在化合物（例如 前药/盐的形成，溶剂/赋形剂优化）用于体内研究；化学的设计/合成 基于亲和力的蛋白质组学的探针。除了这里描述的项目外，我还有其他几个 与癌症中心成员的药物化学合作，这将导致癌症的新方向 治疗和我处于整合CBMM和免疫学计划的项目的独特地位。我的 通过合成化合物的贡献对于同行审查的出版物和赠款申请至关重要。 在过去5年中，我的贡献得到了一些主要发现，包括：（i）合成和 Aurora A-JAK2抑制剂的开发及其在GVHD中的应用； （ii）鉴定新型ACK1 抑制剂； （iii）综合用于评估临界酪氨酸激酶的靶标特异性的化学问题和 PARP抑制剂； （iv）双重BRD4-激酶抑制剂的合成/开发，（v）新型非 - 共价蛋白酶体抑制剂。我坚信本申请中描述的研究项目将 促进新的方向，方法，新的化学问题和药物研究和靶向癌症，我将 我将70％的努力（8.4个日历月）献给了该奖项。