Exploration of Targeted Anti-tumor Therapy (Aug 2020)

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

DOI
https://doi.org/10.37349/etat.2020.00017
Journal volume & issue
Vol. 1, no. 4
pp. 259 – 272

Abstract

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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.

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