PROTACs are effective in addressing the platelet toxicity associated with BCL-XL inhibitors

Peiyi Zhang, Xuan Zhang, Xingui Liu, Sajid Khan, Daohong Zhou, Guangrong Zheng

Research output: Contribution to journalReview articlepeer-review

4 Scopus citations

Abstract

BCL-XL is an anti-apoptotic protein that plays an important role in tumorigenesis, metastasis, and intrinsic or therapy-induced cancer drug resistance. More recently, BCL-XL has also been identified as a key survival factor in senescent cells. Accumulation of senescent cells has been indicated as a causal factor of aging and many age-related diseases and contributes to tumor relapse and metastasis. Thus, inhibition of BCL-XL is an attractive strategy for the treatment of cancer and extension of healthspan. However, development of BCL-XL inhibitors such as navitoclax for clinical use has been challenging because human platelets depend on BCL-XL for survival. In this review, the authors discuss how BCL-XL-targeted proteolysis targeting chimeras (PROTACs) afford a novel approach to mitigate the on-target thrombocytopenia associated with BCL-XL inhibition. The authors summarize the progress in the development of BCL-XL PROTACs. The authors highlight the in vitro and in vivo data supporting that by hijacking the ubiquitin protein ligase (E3) that are poorly expressed in human platelets, BCL-XL PROTACs can significantly improve the therapeutic window compared to conventional BCL-XL inhibitors. These findings demonstrated the potentially broad utility of PROTAC technology to achieve tissue selectivity through recruiting differentially expressed E3 ligases and to reduce on-target toxicity.

Original languageEnglish (US)
Pages (from-to)259-272
Number of pages14
JournalExploration of Targeted Anti-tumor Therapy
Volume1
Issue number4
DOIs
StatePublished - 2020
Externally publishedYes

Keywords

  • Apoptosis
  • BCL-X
  • navitoclax
  • proteolysis targeting chimera
  • thrombocytopenia

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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