May 2025· Nature Communications· Vol 16· 43 citations· 46 references
Medicine
TL;DR
It is demonstrated that linker-free PROTACs can outperform traditional designs, marking a paradigm shift in PROTAC development for targeted protein degradation.
Abstract
Proteolysis-targeting chimeras (PROTACs) present a potentially effective strategy against various diseases via selective proteolysis. How to increase the efficacy of PROTACs remains challenging. Here, we explore the necessity of the linker, which has been deemed as an integral part of heterobifunctional PROTACs. Adopting single amino acid-based degradation signals, we find that the linker is not a required feature of the PROTACs. Notably, the linker-free PROTAC, Pro-BA, exhibits superior efficacy over its linker-bearing counterparts in degrading EML4-ALK and inhibiting lung cancer cell growth, as Pro-BA induces a stronger interaction between the target and the E3 ubiquitin ligase. Pro-BA is a water-soluble, orally administered degrader that significantly inhibits the tumor growth in a xenograft mouse model. The broad applicability of this linker-free PROTAC strategy is further validated through the development of BCR-ABL degrader. Our study introduces a design paradigm for PROTACs, potentially facilitating the advancement of more efficient therapeutic degraders. Linkers are traditionally seen as important for PROTAC activity. Here, the authors demonstrate that linker-free PROTACs can outperform traditional designs, marking a paradigm shift in PROTAC development for targeted protein degradation.
This review summarizes recent advances in chemical protein degradation strategies for neurodegenerative disorders and highlights potential future perspectives of multifunctional PROTACs for therapeutic development.
Pasquale Degennaro, Imane Ghafir El Idrissi, Rosa Purgatorio et al.· Pharmaceuticals· 0 citations
KLHL12 is identified as a potentially tumor-selective E3 ligase and the development of the first-in-class KLHL12-recruiting PROTACs are reported, which established KLHL12 as a promising tumor‑selective E3 ligase and provided a KLHL12-recruiting PROTAC platform for cancer therapy.
Shicheng Xu, Xian Zhang, Shun-Bo Hu et al.· Angewandte Chemie· 0 citations
Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that degrade pathogenic proteins via the ubiquitin-proteasome system. Their event-driven mechanism enables targeting of traditionally undruggable proteins and overcomes acquired resistance through complete protein degradation. Despite these advantages in cancer therapy, clinical translation of PROTACs is hampered by high molecular weight, poor solubility, off-target effects, and the hook effect. To address these challenges, integrating bioorthogonal in situ self-assembly of PROTACs with advanced nanodelivery platforms has emerged as a promising strategy to enhance delivery efficiency, enable spatiotemporally controlled protein degradation, and reduce toxicity. This review systematically outlines design and construction strategies for in situ self-assembling PROTACs, highlighting recent advances in nanodelivery systems that improve solubility, bioavailability, and degradation efficacy while mitigating off-target effects and the hook effect. Finally, we discuss current challenges and future perspectives for PROTACs-based precision cancer therapy.
Pan Liang, Yuying Ren, Yongning Bian et al.· Chemical Communications· 0 citations
Proteolysis-targeting chimeras (PROTACs) are heterobifunctional small molecules that induce selective degradation of disease-associated proteins through the ubiquitin-proteasome system. Rather than transiently inhibiting protein function, PROTACs induce selective elimination of the target protein. This event-driven pharmacological strategy offers significant advantages for targeting proteins that are difficult to modulate using conventional occupancy-driven inhibitors. Since the initial proof-of-concept studies and the entry of the first PROTAC candidates into clinical trials, targeted protein degradation has evolved into a clinically relevant therapeutic platform, particularly in oncology. In this review, we examine how these degraders work and the chemistry involved in their design—from linker optimization to selecting E3 ligases. We also explain how they form the molecular connections needed to function. Representative clinical programs targeting the androgen receptor, estrogen receptor, bromodomain-containing proteins, and Bruton tyrosine kinase are discussed to illustrate current therapeutic progress, remaining challenges, and lessons learned during clinical development. We also explore the hurdles in bringing these to patients, such as large molecular size, solubility, limited cell permeability, pharmacokinetics, tumor resistance, and the complexity of manufacturing. Emerging approaches, including reversible degraders, photoactivatable PROTACs, antibody-directed delivery systems, and artificial intelligence-assisted molecular design, are also highlighted as promising strategies to improve selectivity and drug-like properties. Collectively, these advances establish PROTAC technology as a transformative platform in modern drug discovery while emphasizing the scientific and translational challenges that must be addressed to enable broader clinical application.
Sandip Badadhe, Vikas B. Gawali, Mahesh D. Bhalsing et al.· Discover Chemistry· 0 citations
Targeted protein degradation mediated by antibodies has emerged as a promising strategy for degrading extracellular or membrane-bound proteins. Proteolysis-Targeting Antibodies (PROTABs) are bispecific antibodies specifically designed to induce the degradation of membrane proteins by tethering them to a cell surface E3 ligase, which promotes ubiquitination and subsequent degradation. Recent studies have demonstrated the potential of PROTABs to degrade oncogenic receptors, but their underlying mechanisms remain to be fully elucidated. Here, we investigated the mechanism of action of a HER2-targeting PROTAB comprising an anti-Zinc and RING finger protein 3 (ZNRF3) arm and an anti-receptor tyrosine-protein kinase erbB-2 (HER2) arm. We show that PROTAB induces rapid ternary complex formation, followed by receptor internalization and degradation, resulting in ~ 85% target depletion within 24 h. Mechanistically, ubiquitination enhances but is not strictly required for internalization, and degradation proceeds predominantly through the lysosomal pathway. Notably, ZNRF3 is not codegraded but instead accumulates at the cell surface, while the PROTAB antibody itself is largely recycled. Importantly, target degradation does not consistently translate into growth inhibition, highlighting the role of cellular context and target dependency. Together, these findings provide a mechanistic framework for PROTAB function and inform the rational design of next-generation antibody-based degraders.
Jieyan He, Tao Sun, Mengwen Zhang et al.· The FEBS Journal· 0 citations
This thorough analysis investigates the molecular basis of PROTAC technology, tracking its progression from an elegant intellectual notion to a clinically approved treatment platform and provides a detailed survey of the current clinical landscape.
N. Vijaya Lakshmi Reddy, M. Sarika, V. Deepika et al.· International Journal of Adv...· 0 citations
