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PROTACs Targeting Molecular Targets in Triple-Negative Breast Cancer

Gyas Khan1, Sarfaraz Ahmad2, Md Sadique Hussain3

  • 1Department of Pharmacology and Toxicology, College of Pharmacy, Jazan University, Jazan, Saudi Arabia.

Current Medicinal Chemistry
|September 5, 2025
PubMed

Insights

Proteolysis-targeting chimeras (PROTACs) offer a novel therapeutic strategy for triple-negative breast cancer (TNBC) by degrading key oncoproteins. This approach shows promise in overcoming treatment resistance and improving patient outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Triple-negative breast cancer (TNBC) lacks targeted therapies, relying on conventional treatments with limitations like resistance and toxicity.
  • Current treatments for TNBC, including chemotherapy and immunotherapy, face significant challenges in efficacy and patient safety.
  • Proteolysis-targeting chimeras (PROTACs) represent a new therapeutic modality for degrading disease-causing proteins via the ubiquitin-proteasome system.

Purpose of the Study:

  • To review the application of PROTACs in treating triple-negative breast cancer.
  • To identify key molecular targets for PROTACs in TNBC, including BET proteins, SRC-1, PARP1, FAK, c-Myc, and CDKs.
  • To evaluate the potential of PROTACs to overcome drug resistance and enhance therapeutic efficacy in TNBC.

Main Methods:

  • Literature review focusing on PROTAC technology and its application in TNBC research.
  • Identification of specific PROTAC molecules and their targeted proteins in preclinical TNBC models.
  • Analysis of studies investigating PROTACs' effects on cancer progression, drug resistance, and protein degradation.

Main Results:

  • PROTACs target critical oncoproteins in TNBC, such as BET proteins, SRC-1, PARP1, FAK, c-Myc, and CDKs.
  • Specific PROTACs like BETd-246, ND1-YL2, and pal-pom PROTACs have demonstrated efficacy in reducing TNBC progression and metastasis.
  • PROTACs targeting EZH2, AR, and TRIM24 highlight the versatility of this therapeutic strategy in TNBC.

Conclusions:

  • PROTACs show significant promise for developing more effective and targeted treatments for triple-negative breast cancer.
  • Challenges remain in optimizing PROTAC pharmacokinetics, stability, bioavailability, selectivity, and minimizing toxicity.
  • Advancements in PROTAC design and ongoing clinical research suggest a potential for improved survival and quality of life for TNBC patients.
Keywords:
Breast cancerE3 ubiquitin ligasesTNBC.oncoproteinsprotein degradationtargeted protein degradation

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