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Chemical Proteomic Identification of Druggable Oncogenic Transcription Factors

可药物致癌转录因子的化学蛋白质组学鉴定

基本信息

批准号：
10357900
负责人：
Liron Bar-Peled
金额：
$ 19.24万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2024-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10357900
关键词：
Address Adopted Antineoplastic Agents Applications Grants Binding Proteins Cancer cell line Chemicals Chromatin Clinical Complex Credentialing Cysteine Detection Development Disease Progression Enzymes Genes Genetic Transcription Goals Growth Hour Human Genetics Immunoprecipitation Label Libraries Malignant Neoplasms Maps Mass Spectrum Analysis Metabolic Methods Mutate Oncogenes Oncogenic Organelles Pharmaceutical Preparations Pharmacology Phosphotransferases Physiological Play Protein Family Proteins Proteome Proteomics Research Resolution Role Sampling Site Specificity Speed Technology Validation Work anti-cancer therapeutic anticancer research base cancer cell cancer therapy chemical property chemoproteomics convict detection sensitivity drug development drug discovery established cell line experimental study functional genomics inhibitor insight next generation protein function protein protein interaction small molecule small molecule inhibitor stable cell line stem success targeted treatment tool transcription factor tumorigenesis

项目摘要

Project Summary Advances in human genetics have identified +400 genes that when amplified or mutated promote tumorigenesis. While there has been huge success in developing drugs for kinases and metabolic enzymes deregulated in cancer, they represent only a small fraction of the cancer drivers discovered to date. A major challenge in cancer research is developing drugs for oncogenic drivers. The vast majority (~80%) of these cancer drivers remain undrugged, including one of the largest classes, transcription factors (TFs) which account for ~19% of oncogenes. These TFs are normally required during development, however, are hijacked during tumorigenesis providing malignant cells with the plasticity required for unchecked proliferation. Although these oncogenic TFs have been biologically credentialed, they are historically considered difficult to target with small-molecule inhibitors, limiting the development of transformative cancer therapies. To overcome these challenges in cancer drug discovery and address the clear unmet needs in cancer treatment, our lab adopts state-of-the-art chemical proteomic platforms that both radically expand the druggable protein landscape in cancer and allow us to pinpoint which proteins are amenable to small molecule inhibition. These chemical proteomic technologies combine the specificity of chemical probes which only react with proteinaceous cysteines with the comprehensive analytical scale of next generation proteomics. Cysteines play critical roles in protein function and are the targets of multiple clinically approved inhibitors. By profiling their interaction with covalent drug-like fragments, we recently discovered that a much larger extant of the proteome than originally predicted is amenable to covalent druggability. While these chemical proteomic approaches have transformed our notion of which proteins are druggable, they remain ill-equipped (due to sensitivity of detection) to determine cysteine druggability on low abundance oncogenic transcription factors. In this grant application, we build on our core chemical proteomic platform and incorporate advances in protein and organelle enrichment technologies to prosecute the druggabilty of high-priority oncogenic TFs by developing two conceptually new and complimentary approaches: 1) By isolating chromatin bound proteins, we enrich for active TFs, enabling us to use traditional chemical proteomic approaches to provide a high content map of druggable cysteines in oncogenic TFs. 2) We develop Enrichment Cysteine Druggability Mapping (ECDM) which allows us to systematically immunoprecipitate and enrich low-abundance TFs and rapidly interrogate the druggabilty of cysteines found in these factors in a period of 18 minutes compared to 30 hours using standard approaches. The research proposed herein, takes full advantage of advances in human genetics and functional genomics and combines them with ultra-high throughput chemical proteomic technologies to define the druggability of TF cancer drivers, a critical first step in the development of targeted therapies. If successful, the development of these drug-discovery platforms has the potential to reshape the next-generation of targeted anti-cancer therapeutics.

项目总结