Development of tankyrase-directed PROTACs as novel scaffolding inhibitors

多聚(ADP-核糖基)转移酶Tankyrase(TNKS，TNKS2)控制着一系列与癌症相关的细胞过程，包括Wnt/catenin信号、端粒长度稳态和河马信号1。因此，Tankyrase催化抑制剂正被开发为分子探针和潜在的治疗剂2。到目前为止，所有可用的tankyrase抑制剂都是NAD共底物结合的拮抗剂。由于它们阻断了聚(ADP-核糖)诱导的泛素化和tankyrase及其底物的降解，它们通常会导致tankyrase的强烈积累。因此，催化抑制剂不包含甚至可能加剧最近报道的tankyrase的非催化功能3，4。为了绕过这些潜在的限制，我们正在开发阻断tankyrase及其效应蛋白之间相互作用的化合物，作为研究tankyrase的催化和非催化功能的化学工具。在这个项目中，我们建议优化tankyrase的效应器结合拮抗剂，并将得到的分子进化成新的PROTACs 6，它通过其效应器结合模块而不是其催化结构域与tankyrase结合。与催化抑制剂不同，我们预测这些分子不会触发tankyrase的积累，因此可能更适合PROTAC的开发。我们预计，tankyrase导向的PROTAC将有助于剖析tankyrase作为与癌症和其他病理过程(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。

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.