Development of tankyrase-directed PROTACs as novel scaffolding inhibitors

开发端锚聚合酶导向的 PROTAC 作为新型支架抑制剂

• 批准号: 2893076
• 金额: --
• 依托单位: Institute of Cancer Research
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2893076
• 关键词: Development; tankyrase; directed; PROTACs; novel

The poly(ADP-ribosyl)transferase tankyrase (TNKS, TNKS2) controls a wide range of cancer-relevant cellular processes, including Wnt/catenin signalling, telomere length homeostasis and Hippo signalling1. Hence, tankyrase catalytic inhibitors are being developed as molecular probes and potential therapeutic agents2. All tankyrase inhibitors available to date act as antagonists of NAD+ co-substrate binding. As they block poly(ADP-ribose)-induced ubiquitylation and degradation of tankyrase and its substrates, they typically give rise to strong tankyrase accumulation. Therefore, catalytic inhibitors do not contain, and may even exacerbate, non-catalytic functions of tankyrase that have recently been reported3,4. To circumvent these potential limitations, we are developing compounds that block the interaction between tankyrase and its effector proteins as chemical tools to investigate catalytic vs. non-catalytic functions of tankyrase5. In this project, we propose to optimise effector binding antagonists of tankyrase and evolve the resulting molecules into novel PROTACs6 that engage tankyrase via its effector-binding modules rather than its catalytic domain. Unlike catalytic inhibitors, we predict that such molecules will not trigger the accumulation of tankyrase and may therefore be more suitable for PROTAC development. We envisage that tankyrase-directed PROTACs will help dissect the functions of tankyrase as a key player in numerous processes linked to cancer and other pathologies such as diabetes, neurodegeneration and fibrosis.

聚（ADP-核糖基）转移酶端锚聚合酶（TNKS，TNKS 2）控制着广泛的癌症相关细胞过程，包括Wnt/连环蛋白信号传导，端粒长度稳态和Hippo信号传导1。因此，端锚聚合酶催化抑制剂正被开发为分子探针和潜在的治疗剂2。迄今为止可获得的所有端锚聚合酶抑制剂都充当NAD+共底物结合的拮抗剂。由于它们阻断聚（ADP-核糖）诱导的泛素化和端锚聚合酶及其底物的降解，它们通常引起强的端锚聚合酶积累。因此，催化抑制剂不包含，甚至可能加剧，最近已被证实的端锚聚合酶的非催化功能3，4。为了规避这些潜在的限制，我们正在开发阻断端锚聚合酶及其效应蛋白之间相互作用的化合物，作为研究端锚聚合酶5的催化与非催化功能的化学工具。在这个项目中，我们建议优化端锚聚合酶的效应子结合拮抗剂，并将所得分子进化成新型PROTAC 6，其通过其效应子结合模块而不是其催化结构域参与端锚聚合酶。与催化抑制剂不同，我们预测这些分子不会引发端锚聚合酶的积累，因此可能更适合PROTAC的开发。我们设想，端锚聚合酶导向的PROTAC将有助于剖析端锚聚合酶作为与癌症和其他病理学（如糖尿病、神经变性和纤维化）相关的许多过程中的关键参与者的功能。