PROTACs as novel therapeutics against Mycobacterium tuberculosis: Current progress and future directions.

Targeted protein degradation (TPD) techniques, particularly proteolysis-targeting chimeras (PROTAC) and molecular glue degraders (MGD), have offered novel strategies in drug discovery. With rapid advancement of computer-aided drug design (CADD) and artificial intelligence-driven drug discovery (AIDD) in the biomedical field, a major focus has become how to effectively integrate these technologies into the TPD drug discovery pipeline to accelerate development, shorten timelines, and reduce costs. Currently, the main research directions for applying CADD and AIDD in TPD include: 1) ternary complex modeling; 2) linker generation; 3) strategies to predict degrader targets, activities and ADME/T properties; 4) In silico degrader design and discovery. Models developed in these areas play a crucial role in target identification, drug design, and optimization at various stages of the discovery process. However, the limited size and quality of datasets related to TPD present challenges, leaving room for further improvement in these models. TPD involves the complex ubiquitin-proteasome system, with numerous factors influencing outcomes. Most current models adopt a static perspective to interpret and predict relevant tasks. In the future, it may be necessary to shift toward dynamic approaches that better capture the intricate relationships among these components. Furthermore, incorporating new and diverse chemical spaces will enhance the precision design and application of TPD agents.

Special Focus Issue - Targeted protein degradation: a new paradigm in medicinal chemistry.

Targeted protein degradation is a new aspect in the field of drug discovery. Traditionally, developing an antibiotic includes tedious and expensive processes, such as drug screening, lead optimization, and formulation. Proteolysis-targeting chimeras (PROTACs) are new-generation drugs that use the proteolytic mechanism to selectively degrade and eliminate proteins involved in human diseases. The application of PROTACs is explored immensely in the field of cancer, and various PROTACs are in clinical trials. Thus, researchers have a profound interest in pursuing PROTAC technology as a new weapon to fight pathogenic viruses and bacteria. This review highlights the importance of antimicrobial PROTACs and other similar “PROTAC-like” techniques to degrade pathogenic target proteins (i.e., viral/bacterial proteins). These techniques can perform specific protein degradation of the pathogenic protein to avoid resistance caused by mutations or abnormal expression of the pathogenic protein. PROTAC-based antimicrobial therapeutics have the advantage of high specificity and the ability to degrade “undruggable” proteins, such as nonenzymatic and structural proteins.

Targeted protein degradation (TPD) has emerged as a revolutionary paradigm in drug discovery and development, offering a promising avenue to tackle challenging therapeutic targets. Unlike traditional drug discovery approaches that focus on inhibiting protein function, TPD aims to eliminate proteins of interest (POIs) using modular chimeric structures. This is achieved through the utilization of proteolysis-targeting chimeras (PROTACs), which redirect POIs to E3 ubiquitin ligases, rendering them for degradation by the cellular ubiquitin-proteasome system (UPS). Additionally, other TPD technologies such as lysosome-targeting chimeras (LYTACs) and autophagy-based protein degraders facilitate the transportation of proteins to endo-lysosomal or autophagy-lysosomal pathways for degradation, respectively. Despite significant growth in preclinical TPD research, many chimeras fail to progress beyond this stage in the drug development. Various factors contribute to the limited success of TPD agents, including a significant hurdle of inadequate delivery to the target site. Integrating TPD into delivery platforms could surmount the challenges of in vivo applications of TPD strategies by reshaping their pharmacokinetics and pharmacodynamic profiles. These proteolysis-targeting drug delivery systems (ProDDSs) exhibit superior delivery performance, enhanced targetability, and reduced off-tissue side effects. In this review, we will survey the latest progress in TPD-inspired drug delivery systems, highlight the importance of introducing delivery ideas or technologies to the development of protein degraders, outline design principles of protein degrader-inspired delivery systems, discuss the current challenges, and provide an outlook on future opportunities in this field.

Targeted protein degradation (TPD), a promising therapeutic strategy in drug discovery, has great potential to regulate the endogenous degradation of undruggable targets with small molecules. As vital resources that provide diverse structural templates for drug discovery, natural products (NPs) are a rising and robust arsenal for the development of therapeutic TPD. The first proof-of-concept study of proteolysis-targeting chimeras (PROTACs) was a natural polyketide ovalicin-derived degrader; since then, NPs have shown great potential to promote TPD technology. The use of NP-inspired targeted protein degraders has been confirmed to be a promising strategy to treat many human conditions, including cancer, inflammation, and nonalcoholic fatty liver disease. Nevertheless, the development of NP-inspired degraders is challenging, and the field is currently in its infancy. In this review, we summarize the bioactivities and mechanisms of NP-inspired degraders and discuss the associated challenges and future opportunities in this field.

NanoTAC in targeted protein degradation: Intelligent delivery platforms and synergistic therapeutic paradigms.

Targeted protein degradation (TPD) is a relatively novel drug discovery strategy that could help break through the limitations of traditional small molecule inhibitors. While TPD mostly utilizes diverse E3 ligases to incorporate the ubiquitin‐proteasome system (UPS), cereblon (CRBN) could be considered one of the most successfully adopted E3 ligases. Thus, expanding the scope of CRBN ligands has received tremendous attention to overcome related issues, such as selectivity and druggability. In this study, design and synthesis of novel benzosultam‐based CRBN ligands have been explored by replacement of lactam in lenalidomide with sultam. The sultam‐based ligands showed CRBN binding affinities 2‐20 times stronger than lenalidomide, presumably from additional hydrogen bonds generated from the extra oxygen atom in the sultam group, as supported by docking studies. This research highlights the potential of novel benzosultam CRBN ligands as a new tool for CRBN‐mediated TPD strategies.

Targeted protein degradation (TPD), the ability to control a proteins fate by triggering its degradation in a highly selective and effective manner, has created tremendous excitement in chemical biology and drug discovery within the past decades. The TPD field is spearheaded by small molecule induced protein degradation with molecular glues and proteolysis targeting chimeras (PROTACs) paving the way to expand the druggable space and to create a new paradigm in drug discovery. However, besides the therapeutic angle of TPD a plethora of novel techniques to modulate and control protein levels have been developed. This enables chemical biologists to better understand protein function and to discover and verify new therapeutic targets. This Review gives a comprehensive overview of chemical biology techniques inducing TPD. It explains the strengths and weaknesses of these methods in the context of drug discovery and discusses their future potential from a medicinal chemist's perspective.

Immunotherapy has revolutionized the landscape of cancer treatment, yet its efficacy is often limited by drug resistance, the immunosuppressive tumor microenvironment (TME), and the “undruggable” nature of key immunoregulatory proteins. Targeted protein degradation (TPD) technology, which harnesses cellular degradation machinery to eliminate disease-associated proteins, is emerging as a transformative strategy in the field of tumor immunotherapy. This review systematically summarizes recent advances in various TPD strategies—based on both the ubiquitin-proteasome system (UPS) and the lysosomal pathway, such as proteolysis-targeting chimera (PROTAC), molecular glues, lysosome-targeting chimera (LYTAC), and antibody-based PROTAC (AbTAC)—within the context of cancer immunotherapy. We emphasize how TPD molecules can directly degrade key target proteins, including immune checkpoints, to alleviate immunosuppression, as well as clear critical immunomodulatory factors within the TME, thereby synergistically reversing immunosuppression and enhancing antitumor immunity. Furthermore, this article discusses the rational design, preclinical validation, and clinical translation trends of TPD-based immunotherapeutic agents. Despite encouraging progress, challenges such as tissue selectivity, off-target effects, and delivery efficiency remain to be addressed. Finally, we envision future directions for advancing the application of TPD technology in cancer immunotherapy.

Targeted protein degradation (TPD) is an emerging therapeutic strategy with the potential of targeting undruggable pathogenic proteins. After the first proof-of-concept proteolysis-targeting chimeric (PROTAC) molecule wasreported, the TPD field has entered a new era. In addition to PROTAC, numerous novel TPD strategies have emerged to expand the degradation landscape. However, their physicochemical properties and uncontrolled off-target side effects have limited their therapeutic efficacy, raising concerns regarding TPD delivery system. The combination of TPD and nanotechnology offers great promise in improving safety and therapeutic efficacy. This review provides an overview of novel TPD technologies, discusses their clinical applications, and highlights the trends and perspectives in TPD nanomedicine.

Recent years have seen great advancement of targeted protein degradation technology, in particular, proteolysis targeting chimeras (PROTACs) are now widely used in developing therapeutics for treating cancer. A PROTAC is a heterobifunctional small molecule with three distinct moieties: a ligand to bind a targeted protein of interest (POI), a second ligand to recruit E3 ubiquitin ligase to form a ternary complex, and a linker for bridging the two ligands. Through the E3 ubiquitin ligase pathway, properly designed PROTACs can effectively degrade POIs with high specificity, which can be pathogenic proteins, thus regulate related pathways and inhibit tumor growth. Currently, there is no high-throughput biochemical assay to measure the POI degradation in vitro, hindering the application of the PROTAC technology. Here we report the development of a high-throughput cell based assay to quantitatively measure the endogenous drug target degradation induced by PROTACs. This assay encompasses over 800 cancer cell lines, many of which are CRISPR-engineered ones on common drug targets. A unique feature of our assay is the incorporation of HiBiT short sequence tags on either N-terminal or C-terminal of endogenous protein in E3 ligase matched cell line through site-specific gene homologous recombination technology. By highly specific and sensitive detection of HiBiT tag content in cell lysates with biochemical assay, we can determine target protein degradation by PROTAC treatment. We demonstrate the utility of the assay on a wide array of drug targets including RAS, LDHA, BTK and HPK1, and show that it can accelerate PROTAC drug discovery. Citation Format: Yunpeng Zhai, Ming Tan, Defu Liu, Guoqian Wang, Jinying Ning, Feng Hao. Cell line panel with HIBIT tagged endogenous proteins to accelerate PROTAC drug discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6181.

Targeted protein degradation (TPD) has emerged as a transformative therapeutic strategy for eliminating disease‐associated proteins, with relevance across disorders ranging from cancer to neurodegeneration. Since its inception nearly two decades ago, TPD has attracted strong academic and commercial interest, with multiple candidates advancing into clinical trials. Despite this progress, the field faces persistent challenges, including limited solubility, poor cellular uptake, and unpredictable structure–activity relationship of small‐molecule degraders, which complicate rational design. To address these limitations, alternative platforms such as nanoparticle‐mediated protein degraders (NanoPDs) have gained attention. First reported 17 years ago, NanoPDs harness a diverse array of materials, degradation mechanisms, and linker chemistries to achieve protein clearance through novel pathways. Although promising, their clinical translation remains constrained by barriers such as lysosomal entrapment, protein corona formation, and biocompatibility concerns. In this review, we present a comprehensive overview of the current landscape of nanoparticle‐mediated TPD. We emphasize the design principles underlying nano–bio interfaces and explore the role of proximity‐induced biology as a mechanism for orchestrating protein interactions. Finally, we highlight critical challenges and key questions that must be addressed to fully realize the therapeutic potential of NanoPDs.

Molecular glue degraders (MGDs) have emerged as a transformative modality in the field of targeted protein degradation (TPD), enabling the selective elimination of disease-relevant proteins, including those traditionally considered undruggable. Unlike bifunctional proteolysis-targeting chimeras (PROTACs), MGDs operate through monovalent architectures that induce protein–protein interactions (PPIs) between E3 ligases and neosubstrates, offering advantages in chemical simplicity, cell permeability, and target scope. However, MGD discovery remains serendipitously, and a translational framework that links rational design to predictable selectivity and tissue exposure is still lacking. In this review, we present an integrated framework for advancing next-generation MGDs through three critical dimensions: rational design, specificity optimization, and delivery systems. First, we examined cutting-edge strategies in MGD design, including covalent handle-based reprogramming, PPI-driven stabilization, and multi-site, multi-functional constructs. Second, we explored structure-guided engineering and chemoinformatic models, such as cereblon degron motifs, zone-based design and multiparameter optimization, to improve neosubstrate selectivity while minimizing off-target liabilities. Third, we summarized delivery platforms, including antibody‒drug conjugates, nanoparticle-enabled systems, and folate-mediated targeting, which are primarily intended to improve tissue selectivity and targeted distribution, thereby promoting local tissue accumulation. Finally, we discussed emerging opportunities at the intersection of artificial intelligence, structural biology, and systems pharmacology for accelerating MGD discovery and clinical translation. Collectively, these interdisciplinary insights underscore the therapeutic promise of MGDs and lay the groundwork for their next-generation evolution in precision medicine. This review summarizes emerging strategies for molecular glue degraders, highlighting rational design principles, specificity engineering, and advanced delivery platforms that collectively accelerate selective degradation of undruggable proteins for precision medicine.

Dysregulated eEF2K expression is implicated in the pathogenesis of many human cancers, including triple-negative breast cancer (TNBC), making it a plausible therapeutic target. However, specific eEF2K inhibitors with potent anti-cancer activity have not been available so far. Targeted protein degradation has emerged as a new strategy for drug discovery. In this study, a novel small molecule chemical is designed and synthesized, named as compound C1, which shows potent activity in degrading eEF2K. C1 selectively binds to F8, L10, R144, C146, E229, and Y236 of the eEF2K protein and promotes its proteasomal degradation by increasing the interaction between eEF2K and the ubiquitin E3 ligase βTRCP in the form of molecular glue. C1 significantly inhibits the proliferation and metastasis of TNBC cells both in vitro and in vivo and in TNBC patient-derived organoids, and these antitumor effects are attributed to the degradation of eEF2K by C1. Additionally, combination treatment of C1 with paclitaxel, a commonly used chemotherapeutic drug, exhibits synergistic anti-tumor effects against TNBC. This study not only generates a powerful research tool to investigate the therapeutic potential of targeting eEF2K, but also provides a promising lead compound for developing novel drugs for the treatment of TNBC and other cancers.

A small-molecule degron with a phenylpropionic acid scaffold