@article{Zhang2020,
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, we discuss how BCL-XL-targeted proteolysis targeting chimeras (PROTACs) afford a novel approach to mitigate the on-target thrombocytopenia associated with BCL-XL inhibition. We summarize the progress in the development of BCL-XL PROTACs. We 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.},
author = {Zhang, Peiyi and Zhang, Xuan and Liu, Xingui and Khan, Sajid and Zhou, Daohong and Zheng, Guangrong},
doi = {10.37349/etat.2020.00017},
issn = {2692-3114},
journal = {Exploration of Targeted Anti-tumor Therapy},
keywords = {Apoptosis,BCL-XL,navitoclax,proteolysis targeting chimera,thrombocytopenia},
pages = {259-272},
title = {{PROTACs are effective in addressing the platelet toxicity associated with BCL-XL inhibitors}},
url = {https://www.explorationpub.com/Journals/etat/Article/100217},
volume = {1},
year = {2020}
}