PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics

Sajid Khan, Yonghan He, Xuan Zhang, Yaxia Yuan, Shaoyan Pu, Qingpeng Kong, Guangrong Zheng, Daohong Zhou

Research output: Contribution to journalReview articlepeer-review

79 Scopus citations

Abstract

Using PROteolysis TArgeting Chimeras (PROTACs) to degrade proteins that are important for tumorigenesis has emerged as a potential therapeutic strategy for cancer. PROTACs are heterobifunctional molecules consisting of one ligand for binding to a protein of interest (POI) and another to an E3 ubiquitin (E3) ligase, connected via a linker. PROTACs recruit the E3 ligase to the POI and cause proximity-induced ubiquitination and degradation of the POI by the ubiquitin-proteasome system (UPS). PROTACs have been developed to degrade a variety of cancer targets with unprecedented efficacy against a multitude of tumor types. To date, most of the PROTACs developed have utilized ligands to recruit E3 ligases that are ubiquitously expressed in both tumor and normal tissues. These PROTACs can cause on-target toxicities if the POIs are not tumor-specific. Therefore, identifying and recruiting the E3 ligases that are enriched in tumors with minimal expression in normal tissues holds the potential to develop tumor-specific/selective PROTACs. In this review, we will discuss the potential of PROTACs to become anticancer therapeutics, chemical and bioinformatics approaches for PROTAC design, and safety concerns with a special focus on the development of tumor-specific/selective PROTACs. In addition, the identification of tumor types in terms of solid versus hematological malignancies that can be best targeted with PROTAC approach will be briefly discussed.

Original languageEnglish (US)
Pages (from-to)4909-4924
Number of pages16
JournalOncogene
Volume39
Issue number26
DOIs
StatePublished - Jun 25 2020
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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