Project 3: Targeting MYC in CRC

项目 3：针对 CRC 中的 MYC

基本信息

批准号：
10700857
负责人：
Robert Daniel Beauchamp
金额：
$ 31.76万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-09 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10700857
关键词：
APC mutation Acute Affinity Animals Antineoplastic Agents Attenuated Binding Binding Proteins Biochemistry Biological Biological Markers Biological Models Cancer Center Cancer Model Cells Characteristics Chromatin Clinical Clinical Trials Colorectal Cancer Dose Drug Combinations Drug Design Drug Kinetics Drug or chemical Tissue Distribution Effectiveness Functional disorder Funding Genes Genetic Genome Genomic approach Goals Human Hydrophobicity In Vitro Investigational Drugs KRAS2 gene Lead Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Maximum Tolerated Dose Modeling Molecular Molecular Analysis Monitor Mus Mutation Oncogenic Oncoproteins Outcome Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Play Property Recurrence Reproduction spores Resources Role Safety Scaffolding Protein Series Site Structure Surface Time Toxicokinetics Tumor Promotion Variant cancer cell cancer type candidate marker candidate validation clinical candidate cofactor colon cancer cell line colon cancer patients colon tumorigenesis colorectal cancer prevention colorectal cancer treatment drug discovery drug metabolism drug-like compound efficacy testing efficacy validation improved in vivo in vivo evaluation inhibitor innovation mouse model nanomolar overexpression patient derived xenograft model pharmacodynamic biomarker pharmacologic pre-clinical preclinical safety prevent programs research clinical testing response safety assessment small molecule structural biology tool transcription factor translational goal tumor tumorigenic

项目摘要

PROJECT SUMMARY/ABSTRACT: P3. Targeting MYC Recurring genetic perturbations in colorectal cancer (CRC) activate MYC, an oncogenic transcription factor that features prominently in human cancer. Despite the pervasive involvement of MYC in CRC, and a wealth of studies demonstrating that genetic inhibition of MYC promotes frank tumor regression in mouse model systems, MYC is generally considered undruggable. Indeed, there are currently no drug-like molecules capable of directly blocking MYC function in cancer cells. Recently, however, we presented a new paradigm for target gene recognition by MYC that also created a new opportunity to discover drugs that block MYC function. We found that the stable association of MYC with chromatin depends on its direct interaction with the chromatin scaffolding protein WDR5, which co-localizes broadly with MYC across the genome and facilitates MYC binding to target genes. Structural analysis revealed that MYC binds WDR5 by engaging a shallow, hydrophobic cleft on the surface of WDR5 that is well-suited for drug discovery. The goal of this project is to target the MYC–WDR5 interface to discover a drug that will disable MYC function in CRC by preventing the stable association of MYC with target gene chromatin. This project combines drug discovery, structural biology, medicinal chemistry, biochemistry, and cutting-edge genomic approaches, along with powerful model systems, to identify, refine, and validate drug-like molecules that disrupt the MYC-WDR5 interaction, and to explore their effectiveness as anti-cancer agents against CRC. Within the five year funding period, we intend to produce first-in-class MYC–WDR5 inhibitors that will be fully validated for their utility in treating CRC and ready to proceed to Investigational New Drug (IND)-enabling studies. Successful completion of this project will address a clear unmet clinical need for targeted anti-MYC therapies, which are expected to have broad efficacy against CRCs for which there are only limited treatment options. Drugs discovered in this program will likely also have utility against a wide spectrum of cancer types.

项目摘要/摘要：针对 MYC。结直肠癌 (CRC) 中反复出现的基因扰动会激活 MYC（一种致癌转录因子）尽管 MYC 在结直肠癌中普遍存在，并且在人类癌症中具有显着的特征。研究表明，MYC 的基因抑制可促进小鼠模型中肿瘤的明显消退事实上，目前还没有类似药物的分子。然而，最近我们提出了一种新的范例。 MYC 的靶基因识别也为发现阻断 MYC 功能的药物创造了新的机会。我们发现 MYC 与染色质的稳定结合取决于它与染色质的直接相互作用染色质支架蛋白 WDR5，在整个基因组中与 MYC 广泛共定位，并促进 MYC 与靶基因的结合表明 MYC 通过接合浅层结合 WDR5。 WDR5 表面的疏水性裂缝非常适合药物发现该项目的目标是以 MYC-WDR5 接口为目标，发现一种药物，通过阻止结直肠癌中的 MYC 功能 MYC 与靶基因染色质的稳定关联该项目结合了药物发现、结构生物学、药物化学、生物化学和尖端基因组方法，以及强大的模型系统，识别、精炼和验证破坏 MYC-WDR5 相互作用的药物样分子，并探索它们的作用我们打算在五年资助期内生产出抗癌药物的有效性。一流的 MYC-WDR5 抑制剂，其治疗 CRC 的效用将得到充分验证，并准备好成功完成该项目将解决新药研究 (IND) 的问题。对靶向抗 MYC 疗法的明显未满足的临床需求，预计该疗法将具有广泛的疗效该计划中发现的治疗选择有限的结直肠癌也可能有治疗效果。可用于对抗多种癌症类型。