TY - JOUR
T1 - Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity
AU - He, Yonghan
AU - Zhang, Xuan
AU - Chang, Jianhui
AU - Kim, Ha Neui
AU - Zhang, Peiyi
AU - Wang, Yingying
AU - Khan, Sajid
AU - Liu, Xingui
AU - Zhang, Xin
AU - Lv, Dongwen
AU - Song, Lin
AU - Li, Wen
AU - Thummuri, Dinesh
AU - Yuan, Yaxia
AU - Wiegand, Janet S.
AU - Ortiz, Yuma T.
AU - Budamagunta, Vivekananda
AU - Elisseeff, Jennifer H.
AU - Campisi, Judith
AU - Almeida, Maria
AU - Zheng, Guangrong
AU - Zhou, Daohong
N1 - Funding Information:
This study was supported by US National Institutes of Health (NIH) grants R01CA211963 (D.Z.), R01CA219836 (D.Z.), R56AG056372 (G.Z.), R21CA223371 (G.Z.), R01AG063801 (DZ, GZ, and J.H.E.), R01AR56679 (M.A.), and R01 AG009909 (J Campisi). Unity Biotechnology sponsored the DMPK study for the Bcl-xl PRO-TACs. In addition, we thank all the reviewers for their efforts to review our manuscript.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - Small molecules that selectively kill senescent cells (SCs), termed senolytics, have the potential to prevent and treat various age-related diseases and extend healthspan. The use of Bcl-xl inhibitors as senolytics is largely limited by their on-target and dose-limiting platelet toxicity. Here, we report the use of proteolysis-targeting chimera (PROTAC) technology to reduce the platelet toxicity of navitoclax (also known as ABT263), a Bcl-2 and Bcl-xl dual inhibitor, by converting it into PZ15227 (PZ), a Bcl-xl PROTAC, which targets Bcl-xl to the cereblon (CRBN) E3 ligase for degradation. Compared to ABT263, PZ is less toxic to platelets, but equally or slightly more potent against SCs because CRBN is poorly expressed in platelets. PZ effectively clears SCs and rejuvenates tissue stem and progenitor cells in naturally aged mice without causing severe thrombocytopenia. With further improvement, Bcl-xl PROTACs have the potential to become safer and more potent senolytic agents than Bcl-xl inhibitors.
AB - Small molecules that selectively kill senescent cells (SCs), termed senolytics, have the potential to prevent and treat various age-related diseases and extend healthspan. The use of Bcl-xl inhibitors as senolytics is largely limited by their on-target and dose-limiting platelet toxicity. Here, we report the use of proteolysis-targeting chimera (PROTAC) technology to reduce the platelet toxicity of navitoclax (also known as ABT263), a Bcl-2 and Bcl-xl dual inhibitor, by converting it into PZ15227 (PZ), a Bcl-xl PROTAC, which targets Bcl-xl to the cereblon (CRBN) E3 ligase for degradation. Compared to ABT263, PZ is less toxic to platelets, but equally or slightly more potent against SCs because CRBN is poorly expressed in platelets. PZ effectively clears SCs and rejuvenates tissue stem and progenitor cells in naturally aged mice without causing severe thrombocytopenia. With further improvement, Bcl-xl PROTACs have the potential to become safer and more potent senolytic agents than Bcl-xl inhibitors.
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U2 - 10.1038/s41467-020-15838-0
DO - 10.1038/s41467-020-15838-0
M3 - Article
C2 - 32332723
AN - SCOPUS:85083845562
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1996
ER -