Developing chemical probes for oncogenic signaling pathways

开发致癌信号通路的化学探针

基本信息

批准号：
10733845
负责人：
Harshani R Lawrence
金额：
$ 29.39万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-19 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10733845
关键词：
ACK1 Gene Address Advanced Development Affinity Applications Grants Automobile Driving Award Biology Cancer Center Cancer Center Support Grant Center Core Grants Chemicals Collaborations Communities Comprehensive Cancer Center Development Disease Drug resistance Evaluation Excipients Formulation Goals Human Immune Evasion Leadership Libraries Malignant Neoplasms Medicine Mission Molecular Molecular Immunology Molecular Medicine Multiple Myeloma Mutation Oncogenic PTPN11 gene Peer Review Pharmaceutical Chemistry Pharmaceutical Preparations Phosphotransferases Positioning Attribute Prodrugs Protein-Serine-Threonine Kinases Proteins Proteomics Public Health Publications Research Research Project Grants Resource Allocation Serine Signal Pathway Signal Transduction Sodium Chloride Solvents Specialist Structure Synthesis Chemistry Tumor Promotion United States National Institutes of Health Validation anticancer research chemical synthesis clinical development design drug candidate drug discovery drug synthesis drug-like compound experience in vivo inhibitor lead optimization leukemia malignant breast neoplasm member mutant novel novel strategies novel therapeutics patient population precision medicine preclinical study programs scale up small molecule targeted treatment treatment strategy tumor growth

项目摘要

Abstract: The goal of the NCI Research Specialist Award prepared by Dr. Harshani Lawrence “Developing chemical probes for oncogenic signaling pathways” will promote identification of small molecules/chemical probes for cancer targets to elucidate underlying molecular mechanisms driving cancer and drug discovery research at the Moffitt Cancer Center (Moffitt). Dr. Lawrence, a synthetic/medicinal chemist with over 20 years of cancer research experience, is the Scientific and Managing Director of the Chemical Biology Core (CBC) at Moffitt. Dr. John Cleveland, Center Director of the Moffitt NCI-designated Comprehensive Cancer Center and PI/PD of the Cancer Center Support Grant (CCSG) P30 CA076292 will serve as the Unit Director for this R50 NCI Research Specialist Award and provide leadership, guidance and be responsible for executive oversight and resource allocation to the CBC. The 4 projects described in this proposal will involve synthesis of drug-like compounds that are inhibitors of the 1. ACK1 and 2. ULK3 serine/threonine kinases, 3. Development of bifunctional gilteritinib degraders, and 4. Validation of novel inhibitors of PERK. The synthetic chemistry strategies/approaches described in this proposal will generate novel compounds to address significant challenges in several types of human cancers. Evaluation of novel, potent and selective inhibitors of ACK1 to target PTPN11-mutant cancers that harbor SHP2 (PTPN11) mutations and breast cancer will generate novel compounds for advanced pre-clinical studies. Potent and selective ULK3 inhibitors will lead to our understanding of drug resistance in Multiple myeloma and novel strategies for treatment of the disease. The synthesis and validation of bifunctional molecules as PROTACs for gilteritinib is expected to advance the field/help to define tractable targets for leukemia. Synthesis/validation of novel potent inhibitors of protein ER kinase (PKR)-like ER kinase (PERK) to reduce tumor promoted immune evasion and thereby reduce tumor growth. As part of this award, Dr. Lawrence 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/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, she is involved in several other medicinal chemistry collaborations with Cancer Center members, and she is in a unique position to integrate projects from the Molecular Medicine and Immunology programs. Dr. Lawrence’s contribution via synthesis of compounds is essential for peer reviewed publications and grant applications. The research projects/strategies described in this application will facilitate new directions, approaches, chemical probes /drugs to study and target cancer.

摘要：Harshani Lawrence博士准备的NCI研究专家奖的目标“发展致癌信号通路的化学问题”将促进小分子/化学的鉴定癌症目标的问题阐明了驱动癌症和药物发现的基本分子机制莫菲特癌症中心（Moffitt）的研究。劳伦斯博士，一位超过20多个合成/药物化学家多年的癌症研究经验，是化学生物学核心的科学和董事总经理（CBC）在莫菲特。 Moffitt NCI指定的综合癌症中心主任John Cleveland博士癌症中心支持补助金（CCSG）的中心和PD P3076292将担任单位主任这项R50 NCI研究专家奖，并提供领导，指导并负责执行监督和资源分配给CBC。本提案中描述的4个项目将涉及合成类似药物的化合物是1。ACK1和2。ULK3丝氨酸/苏氨酸激酶的抑制剂，3。双功能吉尔替替尼的发展，以及4。验证新型PERK抑制剂。合成本提案中描述的化学策略/方法将产生新颖的化合物来解决在几种类型的人类癌症中面临重大挑战。评估新颖，潜在和选择性抑制剂 ACK1靶向具有SHP2（PTPN11）突变和乳腺癌的PTPN11突变癌生成新的化合物，用于晚期临床前研究。有效和选择性ULK3抑制剂将导致我们对多发性骨髓瘤的耐药性的理解以及治疗该疾病的新型策略。双功能分子的合成和验证作为吉尔特替尼的protacs的合成和验证。领域/帮助定义白血病的可牵引目标。新型蛋白有效抑制剂的合成/验证 ER激酶（PKR）类似ER激酶（PERK）减少肿瘤促进免疫驱虫，从而减少肿瘤生长。作为该奖项的一部分，劳伦斯博士将继续为莫菲特研究社区提供关键启用化学生物学支持。这将包括基于结构的设计和集合库的合成（命中率优化）确定新化合物/化学问题，以探索分子机制参与癌症的蛋白质；潜在化合物的扩大合成/配方（例如前药/盐的形成，用于体内研究的溶剂/赋形剂优化）；基于亲和力的化学问题的设计/合成蛋白质组学。除了这里描述的项目外，她还参与了其他几种药物化学与癌症中心成员的合作，她处于独特的位置，可以整合来自分子医学和免疫学计划。劳伦斯博士通过合成化合物的贡献是对同行审查的出版物和赠款申请必不可少。所描述的研究项目/策略该应用将促进新的方向，方法，化学问题 /药物研究和靶向癌症。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Deubiquitinase Vulnerabilities Identified through Activity-Based Protein Profiling in Non-Small Cell Lung Cancer.

通过非小细胞肺癌中基于活性的蛋白质分析鉴定去泛素酶漏洞。

DOI：
10.1021/acschembio.2c00018
发表时间：
2022
期刊：
ACS chemical biology
影响因子：
4
作者：
Mahajan,Shikha;Majumder,Anurima;Stewart,PaulA;Chen,YianAnn;Adhikari,Emma;Fang,Bin;Yang,Yan;Lawrence,Harshani;Kinose,Fumi;Koomen,JohnM;Haura,EricB
通讯作者：
Haura,EricB