Homobivalent, Trivalent, and Covalent PROTACs: Emerging Strategies for Protein Degradation

Proteolysis-targeting
chimeras (PROTACs) is a fast-growing technology
providing many strengths over inhibition of protein activity directly
and is attracting increasing interest in new drug discovery and development.
However, efficiently identifying potent and drug-like degraders is
still challenging in the development of PROTACs. Complementary to
traditional PROTACs, several emerging types of PROTACs, such as homobivalent
PROTACs based on two E3 ligases (e.g., CRBN, VHL, MDM2, TRIM24), chemical-
or biological-based trivalent/multitargeted PROTACs, and covalent
PROTACs, are rising for targeted protein degradation. These new types
of PROTACs have several advantages over the traditional PROTACs including
high selectivity, low toxicity, better therapeutic effects, and so
on. In this perspective, we will summarize the latest development
of representative PROTACs focusing on research mainly in past 10 years
and discuss their advantages and disadvantages. Moreover, the outlook
and perspectives on the associated challenges and future directions
will be provided.

蛋白质降解靶向嵌合体（PROTACs）技术作为一项迅速发展的前沿技术，在直接抑制蛋白质活性方面展现出诸多优势，因而日益受到新药发现与开发领域的广泛关注。然而，在PROTACs的开发过程中，高效识别具有强效及药物特性的降解剂仍然是一项挑战。作为传统PROTACs的补充，多种新型PROTACs技术应运而生，例如基于两种E3连接酶（如CRBN、VHL、MDM2、TRIM24）的同源双价PROTACs、基于化学或生物学的三价/多靶点PROTACs以及共价PROTACs，这些新型PROTACs在靶向蛋白质降解方面展现出相较于传统PROTACs的若干优势，包括高选择性、低毒性、更佳的疗效等。在本篇综述中，我们将总结过去十年内代表性PROTACs的最新研究进展，并探讨其优缺点。此外，还将展望相关挑战及未来的发展方向。