Chen Yong, Xia Zihan, Suwal Ujjwal, Rappu Pekka, Heino Jyrki, De Wever Olivier, De Geest Bruno G
Department of Pharmaceutics, Ghent University 9000 Ghent Belgium
Cancer Research Institute Ghent 9000 Ghent Belgium.
Chem Sci. 2024 Oct 2;15(42):17691-701. doi: 10.1039/d4sc03555k.
Proteolysis targeting chimeras (PROTACs) are revolutionizing the drug development landscape due to their unique ability to selectively degrade disease-associated proteins. Conventional PROTACs are bivalent entities that induce ubiquitination and subsequent proteolysis of a chosen protein of interest (POI) by forming a ternary complex with an E3 ligase. We hypothesized that dual-ligand PROTACs, featuring two copies each of a POI ligand and an E3 ligase ligand, would facilitate the formation of high-avidity, long-lived ternary complexes inside cells, thereby increasing POI degradation potency. To this end, we developed a convergent synthesis route, using l-aspartic acid as a building block for homodimer synthesis, followed by copper-catalyzed azide-alkyne cycloaddition (CuAAC) to conjugate both dimers through a flexible linker. Dual-ligand PROTACs achieved up to a tenfold increase in degradation efficiency and a hundredfold increase in cytotoxicity across various cancer cell lines compared to their single-ligand counterparts. Furthermore, dual-ligand PROTACs sustain prolonged protein degradation, up to 60 hours after pulsing and washout. , in a mouse tumor model, the superior therapeutic activity of dual ligand PROTACs was observed.
靶向蛋白降解嵌合体（PROTACs）正彻底改变药物研发格局，因其具有选择性降解疾病相关蛋白的独特能力。传统的PROTACs是二价实体，通过与E3连接酶形成三元复合物来诱导所选目标蛋白（POI）的泛素化及随后的蛋白水解。我们推测，具有两个POI配体拷贝和两个E3连接酶配体拷贝的双配体PROTACs，将有助于在细胞内形成高亲和力、长寿命的三元复合物，从而提高POI降解效力。为此，我们开发了一种收敛合成路线，使用L-天冬氨酸作为同二聚体合成的构建模块，随后通过铜催化的叠氮化物-炔烃环加成反应（CuAAC），通过柔性接头将两个二聚体连接起来。与单配体PROTACs相比，双配体PROTACs在各种癌细胞系中的降解效率提高了十倍，细胞毒性提高了百倍。此外，双配体PROTACs能持续延长蛋白降解时间，在脉冲和洗脱后长达60小时。在小鼠肿瘤模型中，观察到双配体PROTACs具有卓越的治疗活性。
