TY  - JOUR
T1  - PROTACs are effective in addressing the platelet toxicity associated with BCL-XL inhibitors
A1  - Zhang, Peiyi
A1  - Zhang, Xuan
A1  - Liu, Xingui
A1  - Khan, Sajid
A1  - Zhou, Daohong
A1  - Zheng, Guangrong
Y1  - 2020///
KW  - Apoptosis
KW  - BCL-XL
KW  - navitoclax
KW  - proteolysis targeting chimera
KW  - thrombocytopenia
JF  - Exploration of Targeted Anti-tumor Therapy
VL  - 1
SP  - 259
EP  - 272
DO  - 10.37349/etat.2020.00017
UR  - https://www.explorationpub.com/Journals/etat/Article/100217
N2  - 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.
ER  -