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Targeted protein posttranslational modifications by chemically induced proximity for cancer therapy

Yunhua Peng1, Jing Liu2, Hiroyuki Inuzuka2

  • 1Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA; The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Center for Mitochondrial Biology and Medicine, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China.

The Journal of Biological Chemistry
|March 4, 2023
PubMed

Insights

Targeting protein modifications with chemical inducers of proximity (CIPs) offers a precise therapeutic strategy. This approach aims to minimize side effects by specifically regulating disease-related proteins, advancing cancer treatment.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Post-translational modifications (PTMs) are crucial for protein function and are implicated in diseases like cancer.
  • Current drugs targeting PTM regulators (e.g., kinases) can cause off-target toxicity due to broad substrate specificity.
  • There is a need for targeted therapies that specifically modulate PTMs on disease-relevant proteins.

Purpose of the Study:

  • To explore chemically induced proximity (CIPs) as a novel therapeutic strategy for precise PTM regulation.
  • To highlight the potential of CIPs in overcoming the limitations of traditional PTM-targeting drugs.
  • To emphasize the development of new CIPs for a wider range of PTMs to enhance cancer treatment.

Main Methods:

  • Review of existing literature on PTMs, their regulators, and therapeutic targeting strategies.
  • Analysis of the mechanism and application of chemical inducers of proximity (CIPs).
  • Discussion of current examples of CIPs (e.g., PROTACs, MGDs) in clinical trials and potential future directions.

Main Results:

  • CIPs enable targeted regulation of specific protein PTMs, including ubiquitination, phosphorylation, acetylation, and glycosylation.
  • CIPs demonstrate potential for precise therapeutic effects with reduced off-target toxicity compared to traditional inhibitors.
  • Several CIP-based drugs are advancing through clinical trials, showing promise for therapeutic translation.

Conclusions:

  • Chemically induced proximity represents a powerful approach for targeted protein PTM modulation.
  • Developing novel CIPs for all PTM types, including methylation and palmitoylation, is essential for comprehensive therapeutic applications.
  • CIPs hold significant promise for advancing cancer treatment and other diseases by offering targeted and safer therapeutic options.
Keywords:
AceTAGDUBTACPHICSPROTACPhoRCPhosTACcancer therapychemically induced proximitymolecular glueposttranslational modification (PTM)

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