Authors
Hannah Lalengzuali Fanai, Basuvan Babu, Kalirajan Rajagopal, Gowramma Byran
Published in
Molecular biology reports. Volume 53. Issue 1. Oct 16, 2026. Epub Oct 16, 2026.
Abstract
Breast cancer is one of the most significant health issues in the world, and resistance to treatment and a lack of targets that can be addressed with drugs limit the effectiveness of the existing treatment options. The development of proteolysis-targeting chimeras (PROTACs) has shifted the concept of occupancy-based inhibition toward event-based targeted protein degradation. Avoiding ubiquitin-proteasome hijacking, PROTACs target disease-relevant proteins to E3 ligases, allowing them to be catalytically degraded, thereby eliminating formerly undruggable or resistant targets. Their modular design, consisting of a warhead, linker, and E3 ligase ligand, eases rational design, but there are still difficulties, including hook effects, poor pharmacokinetics, and off-target toxicity. PROTACs have been known to undergo evolution, such as PHOTACs, CLIPTACs, and RIBOTACs, which have expanded therapeutic approaches. Clinical trial molecules such as ARV-471 have demonstrated an effective role in the degradation of ER+, showcasing their broader significance in HER2 by degrading BRD4, CDK, and PD-L1. However, a knowledge gap exists that limits our understanding of E3 ligases, constraining their tissue specificity and metabolism. Prospective directions focus on computational strategies to design E3 ligase-based PROTAC prodrugs, nanostructured PROTACs, and test them in vivo using organoids and xenograft models. Overall, PROTACs can become a novel therapeutic approach in the treatment of breast cancer.
PMID:
42886396
Bibliographic data and abstract were imported from PubMed on 17 Oct 2026.
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