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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：
10576274
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 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10576274
关键词：
Acceleration Address Adopted Antineoplastic Agents Applications Grants Binding 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 Phosphotransferases Physiological Play Proliferating Protein Family Proteins Proteome Proteomics Reaction Research Resolution Role Sampling Shapes Site Specificity Speed Technology Validation Work anti-cancer therapeutic anticancer research 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 pharmacologic 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.

项目摘要人类遗传学的进步已经确定了400多个基因，当扩增或突变时会促进肿瘤发生。虽然在开发针对激酶和代谢酶失调的药物方面取得了巨大成功，虽然它们与癌症的关系密切，但它们仅代表迄今为止发现的癌症驱动因素的一小部分。癌症的一个主要挑战研究人员正在开发针对致癌驱动因素的药物。这些癌症驱动因素中的绝大多数（约80%）仍然存在不规则的，包括最大的类别之一，转录因子（TF），占~19%，致癌基因这些转录因子在发育过程中通常是必需的，然而，在肿瘤发生过程中被劫持。为恶性细胞提供不受抑制的增殖所需的可塑性。虽然这些致癌TF 虽然它们已经获得生物学认证，但历史上认为它们难以用小分子靶向抑制剂，限制了变革性癌症疗法的发展。为了克服癌症的这些挑战，药物发现和解决癌症治疗中明显未满足的需求，我们的实验室采用了最先进的化学蛋白质组学平台，既从根本上扩大了癌症中的可药用蛋白质景观，哪些蛋白质易于受到小分子抑制。这些化学蛋白质组学技术联合收割机仅与蛋白质半胱氨酸反应的化学探针的特异性，下一代蛋白质组学的规模。半胱氨酸在蛋白质功能中起着关键作用，并且是多种蛋白质的靶点。临床批准的抑制剂。通过分析它们与共价药物样片段的相互作用，我们最近发现比最初预测的更大的蛋白质组的存在是可以共价结合的。可用药性虽然这些化学蛋白质组学方法已经改变了我们对哪些蛋白质是尽管半胱氨酸是可药用的，但它们仍然装备不良（由于检测灵敏度），无法在低浓度下确定半胱氨酸的可药用性。丰富的致癌转录因子。在这个拨款申请中，我们建立在我们的核心化学蛋白质组学基础上，平台，并结合蛋白质和细胞器富集技术的进展，通过开发两种概念上新的和互补的方法来研究高优先级致癌TF的药物可药性： 1)通过分离染色质结合蛋白，我们富集了活性TF，使我们能够使用传统的化学方法，蛋白质组学方法来提供致癌TF中可药用半胱氨酸的高含量图谱。2)我们开发富集半胱氨酸药敏图谱（ECDM），使我们能够系统地免疫沉淀，富集低丰度的TF，并在一段时间内快速询问在这些因子中发现的半胱氨酸的可药用性，与标准方法的30小时相比，本文提出的研究，需要充分利用人类遗传学和功能基因组学的进步，并将其与超高通过化学蛋白质组学技术来确定TF癌症驱动因素的可药用性，这是关键的第一步，靶向治疗的发展。如果成功的话，这些药物发现平台的发展将重塑下一代靶向抗癌疗法的潜力。