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PROTAC'ing oncoproteins: targeted protein degradation for cancer therapy

Jeremy M Kelm1, Deepti S Pandey1, Evan Malin1

  • 1Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences (EACPHS), Wayne State University, Detroit, MI, 48201, USA.

Molecular Cancer
|March 29, 2023
PubMed

Insights

Proteolysis targeting chimeras (PROTACs) offer a novel approach to cancer therapy by degrading target proteins, overcoming resistance to molecularly targeted therapies and addressing challenging oncoproteins.

Area of Science:

  • Oncology
  • Molecular Biology
  • Medicinal Chemistry

Background:

  • Molecularly targeted cancer therapies improve outcomes but face durability limitations due to acquired resistance.
  • Existing targeted therapies have limited coverage for certain challenging oncoproteins.
  • Protein degraders represent a new therapeutic modality that depletes target proteins.

Purpose of the Study:

  • To review the development of proteolysis targeting chimeras (PROTACs) for cancer therapy.
  • To discuss the biological activities and medicinal chemistry of PROTAC design.
  • To highlight the potential of PROTACs to overcome limitations of traditional targeted therapies.

Main Methods:

  • Review of existing literature on PROTAC development and applications in cancer therapy.
  • Analysis of medicinal chemistry strategies employed in PROTAC design.
  • Evaluation of reported biological activities and therapeutic potential of PROTACs.

Main Results:

  • PROTACs demonstrate advantages including resiliency to mutations, enhanced selectivity, and lower dosing.
  • PROTACs can target oncogenic transcription factors and scaffolding proteins previously difficult to inhibit.
  • Recent advances in PROTAC design are enabling more rational development strategies.

Conclusions:

  • PROTACs represent a promising therapeutic strategy for cancer, offering a way to overcome resistance mechanisms.
  • The field of PROTAC development is rapidly advancing, paving the way for new rational degrader designs.
  • PROTACs have the potential to expand the scope of targeted cancer therapy.

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