Advances in molecular biology and proteomics have revealed the central position of dysregulated proteins in driving human illness [1]. Consequently, eliminating or disabling pathogenic proteins has grow to be a cornerstone of contemporary drug discovery. Conventional small-molecule therapeutics usually act by binding to useful pockets on the right track proteins to inhibit exercise [2]. For example, tyrosine kinase inhibitors (TKIs) focusing on BCR-ABL have considerably improved survival in sufferers with continual myeloid leukemia (CML) [3]. Nonetheless, the overwhelming majority of proteins—estimated at over 80 % of the human proteome—lack accessible ligandable websites and stay past the attain of standard inhibitors [4]. Moreover, small molecules typically interact off-targets, contributing to toxicity and resistance. These limitations are particularly problematic in multifactorial ailments equivalent to most cancers and neurodegeneration, the place perturbations in advanced protein networks require broader therapeutic attain [5].
Focused protein degradation (TPD) gives a paradigm-shifting technique by redirecting endogenous degradation equipment—primarily the ubiquitin-proteasome system and lysosomal-autophagy pathways—to selectively take away disease-relevant proteins [6]. Not like occupancy-driven inhibitors that require sustained high-affinity engagement, TPD depends on event-driven mechanisms the place transient binding suffices to set off irreversible degradation [7]. This mechanism allows potent efficacy at low doses and permits for degradation of non-enzymatic scaffolds and scaffolding capabilities inaccessible to classical inhibitors.
Over the previous 20 years, TPD has advanced into a various and modular platform encompassing proteolysis-targeting chimeras (PROTACs), molecular glues (MGs), lysosome-targeting chimeras (LYTACs), autophagy-targeting chimeras (AUTACs), autophagosome-tethering compounds (ATTECs), and different rising modalities (Fig. 1). These methods vastly increase the druggable proteome and are more and more being translated into medical purposes.
On this assessment, we systematically hint the developmental trajectory and analysis advances of TPD applied sciences. First, we start with the ubiquitin-proteasome system and the lysosomal-autophagic pathway, elucidating their molecular mechanisms and organic foundations as core degradation pathways, thereby establishing a framework for understanding TPD’s mode of motion. Subsequently, we concentrate on summarizing the design ideas, benefits, and newest medical advances of main technical platforms. These embrace more and more mature bifunctional molecules like PROTACs, MGs that induce protein interactions through single small molecules, antibody-conjugated degradation methods, and varied rising autophagy-related approaches (e.g., AUTACs, ATTECs). Constructing on this basis, we additional explored how progressive approaches—equivalent to linker arm engineering, enlargement of E3 ligase sources, controllable responsive module design, and nanocarriers—drive optimization and breakthroughs in TPD selectivity, pharmacokinetics, and therapeutic breadth. Lastly, integrating the newest medical and frontier analysis, we conduct an in-depth evaluation of TPD’s software prospects in main illness areas together with most cancers, neurodegenerative ailments, cardiovascular ailments, and infectious ailments. We additionally summarize and venture key challenges in drug supply, off-target impact management, and security analysis. By means of this multidimensional assessment, we intention to disclose the strategic worth of TPD expertise in precision drugs and new drug growth, offering insights and inspiration for its future route.
