Novel bifunctional chemistries for unbiased exploration of targeted protein degradation mechanisms

能够选择性地靶向蛋白质进行降解的小分子，与简单地抑制其功能相反，被证明是生命科学家了解广泛细胞功能的宝贵研究工具，并为新一代突破性治疗提供了潜力。蛋白水解靶向嵌合体（Proteolysis Targeting Chimeras，PROTAC）是双头分子，其通过同时用一个头与靶蛋白结合并且用另一个头与E3泛素连接酶结合，从而诱导靶蛋白的接近和泛素化/降解来实现该目标。迄今为止，这些方法已被广泛用于理解和治疗癌症[1]。应用这些或类似的工具来理解更广泛的生物学背景受到对泛素蛋白酶体系统（UPS）可以被重定向以降解所选择的靶蛋白的机制的狭隘理解的限制。这种限制在中枢神经系统中尤其严重，中枢神经系统中存在特定的蛋白质表达特征和小分子组织可及性的额外挑战，这些挑战限制了经典靶向蛋白质降解方法的适用性。该项目将专注于开发创新的化学库合成和测试方法，以提供选择性降解与广泛神经功能有关的蛋白质的工具，以一种无偏的方式。这将使我们能够探索新的概念，这些概念有可能改变我们对UPS如何在中枢神经系统内被利用和有目的地引导的理解。为了实现这一目标，将开发方法和试剂，这些方法和试剂将在目前追求邻近诱导模式（包括但不限于靶向蛋白质降解）的许多生命科学研究小组和组织中找到实用性。

Small molecules that can selectively target proteins for degradation, as appose to simply inhibiting their function, are proving to be invaluable research tools for life scientists to understand a wide range of cellular function and provide the potential for a new generation of breakthrough therapeutics. Proteolysis Targeting Chimeras (PROTACs) are two-headed molecules that achieve this goal by simultaneously binding with one head to a target protein and with another head to an E3 ubiquitin ligase, thus inducing the proximity and ubiquitination/degradation of the target protein. Such approaches to date have been largely utilised in the context of understanding and treating cancer [1]. Application of these or similar tools to understand a broader array of biological contexts is limited by a narrow understanding of mechanisms via which the ubiquitin proteasome system (UPS) can be re-directed to degrade a chosen target protein. This limitation is particularly acute in the central nervous system where there are specific protein expression signatures and additional challenges for small molecule tissue accessibility that limit applicability of classical targeted protein degradation approaches.This project will focus on developing innovative chemical library synthesis and testing approaches to deliver tools that selectively degrade protein(s) implicated in a wide range of neuronal function, in a mechanism unbiased fashion. This will enable exploration of novel concepts that have potential to transform our understanding of how the UPS can be harnessed and purposefully directed within the central nervous system. To achieve this goal methods and reagents will be developed that will find utility amongst the many life science research groups and organisations currently pursuing proximity inducing modalities, including but not limited to targeted protein degradation.