Translating novel cancer targets and mechanisms from the CTD^2 Network using molecular glues

项目总结 我们目前的CTD2网络中心发现，许多癌症在药物治疗后出现了稳定的 细胞状态耐凋亡，易受铁性下垂的影响。在努力翻译这些发现的同时， 以及整个网络的其他发现的结果，我们认识到CTD2网络的核心需求 适应新的药物发现方法。在这里，我们描述了在计算和实验方面的进展 从合成有机材料的新用途中发现小分子粘合剂和分子胶 化学，DNA条形码，亲和力筛选后丰富条形码的计算分析，以及 化学生物学分析。我们的战略基于这样一个发现：小分子胶水可以将 这两种蛋白质在其他情况下是不相关的。我们将利用DNA条形码化合物来发现类药物 分子胶：1)降解选择性，2)组织选择性，3)癌基因选择性。这项建议 旨在开发新的方法来转换CTD2网络发现的难治性癌症漏洞 走向新的治疗方法。这种方法产生的分子胶具有目前无法获得的活性。 药物发现方法，并制定系统地发现癌症降解物的蓝图 脆弱性、组织限制性酶抑制剂和恢复蛋白质-蛋白质关联的化合物 因致癌基因突变而受损。在目标1中，我们将开发新的能力来识别特定的提示者蛋白质 并发现分子胶。在目标2中，我们将使用DNA条形码发现新的分子胶 技术在目标3中，我们将确定在体外和细胞内的作用机制，并参与CTD2网络 中心，以补充我们的化学生物学专业知识。这些化合物将作为发射台，以告知 癌症的脆弱性，以及在化学优化后，特定癌症类型的治疗假说。 该项目的成功成果包括识别新的化学物质以针对重要的基因 癌症的靶点，建立CTD2网络可用的新的和强大的资源，并有可能 一种新的药物发现模式。

PROJECT SUMMARY Our current CTD2 Network Center discovered that many cancers, following drug treatment, emerge in a stable cell state resistant to apoptosis and vulnerable to ferroptosis. While pursuing efforts to translate these findings, and the findings of other discoveries throughout the Network, we recognized a central need for the CTD2 Network to adapt new methods of drug discovery. Here, we describe computational and experimental advances in the discovery of small-molecule binders and molecular glues emerging from the novel use of synthetic organic chemistry, DNA barcoding, computational analyses of enriched barcodes following affinity-based screens, and chemical biology assays. We base our strategy on the discovery that small-molecule glues can bring together two proteins that do not otherwise associate. We will exploit DNA-barcoded compounds to discover drug-like molecular glues that are: 1) degradation-selective, 2) tissue-selective, and 3) oncogene-selective. This proposal aims to develop novel methods to translate CTD2 Network discoveries of difficult-to-drug cancer vulnerabilities towards novel therapeutics. The methods yield molecular glues that confer activities not available by current drug-discovery methods, and to develop a blueprint to discover systematically degraders for cancer vulnerabilities, tissue-restricted enzyme inhibitors, and compounds that restore protein–protein associations impaired by oncogenic mutation. In Aim 1, we will develop novel capabilities to identify specific presenter proteins and to discover molecular glues. In Aim 2, we will discover novel molecular glues using DNA-barcoding technology. In Aim 3, we will determine mechanism of action in vitro and in cells and engage CTD2 Network Centers to complement our chemical biology expertise. These compounds will serve as launching pads to inform cancer vulnerabilities and, upon chemical optimization, therapeutic hypotheses in specific cancer types. Successful outcomes of this project include the identification of new chemical matter to target important genetic targets in cancer, establishment of a novel and powerful resource available to the CTD2 Network, and potentially a new paradigm for drug discovery.