Liu Yue, Yang Tao, Huang Lei, Li Shengrong, Liu Tongzheng, Tan Yi, Li Zhengqiu
State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China.
International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development (MOE), Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China.
Angew Chem Int Ed Engl. 2025 Jul 2:e202508538. doi: 10.1002/anie.202508538.
Targeted protein degradation (TPD) has been recognized as a powerful therapeutic strategy for the treatment of a wide range of diseases. However, the application of existing degraders is constrained by their dependence on a limited number of E3 ubiquitin ligases, such as CRBN and VHL. To address this limitation, we developed a suite of novel small-molecule degraders by integrating an ynamide electrophile into protein-targeting ligands. These compounds demonstrated remarkable target degradation capability. Subsequent proteome profiling and functional validation revealed that Cys97 residue of retinoblastoma binding protein 7 (RBBP7) E3 ligase was covalently engaged and responsible for the degradation mechanism. Furthermore, the ynamide motif has proved to be a versatile and transplantable chemical handle, facilitating the development of degraders targeting a wide range of proteins, including CDK4, PDE5, PI3K, AKT, BCR-ABL, BRD4, EGFR, and EGFR. Notably, incorporation of ynamide into the "pan-kinase" inhibitor XO44 yielded degraders capable of simultaneously degrading various kinases, such as PI3K, Syk, AKT, and GSK-3β, further highlighting the general feasibility of this approach. Importantly, the ynamide-containing degraders demonstrated significantly enhanced anticancer potency compared to their parent inhibitors.
靶向蛋白质降解（TPD）已被公认为是治疗多种疾病的一种强有力的治疗策略。然而，现有降解剂的应用受到其对有限数量的E3泛素连接酶（如CRBN和VHL）的依赖性的限制。为了解决这一限制，我们通过将炔酰胺亲电试剂整合到蛋白质靶向配体中，开发了一套新型小分子降解剂。这些化合物表现出显著的靶向降解能力。随后的蛋白质组分析和功能验证表明，视网膜母细胞瘤结合蛋白7（RBBP7）E3连接酶的Cys97残基被共价结合并负责降解机制。此外，炔酰胺基序已被证明是一种通用且可移植的化学基团，有助于开发针对多种蛋白质的降解剂，包括CDK4、PDE5、PI3K、AKT、BCR-ABL、BRD4、EGFR和EGFR。值得注意的是，将炔酰胺掺入“泛激酶”抑制剂XO44中产生了能够同时降解多种激酶（如PI3K、Syk、AKT和GSK-3β）的降解剂，进一步突出了该方法的普遍可行性。重要的是，与它们的母体抑制剂相比，含炔酰胺的降解剂表现出显著增强的抗癌效力。
