Discovery of PROTAC BCL-XL degraders as potent anticancer agents with low on-target platelet toxicity

Xuan Zhang, Dinesh Thummuri, Xingui Liu, Wanyi Hu, Peiyi Zhang, Sajid Khan, Yaxia Yuan, Daohong Zhou, Guangrong Zheng

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

Abstract

Anti-apoptotic protein BCL-XL plays a key role in tumorigenesis and cancer chemotherapy resistance, rendering it an attractive target for cancer treatment. However, BCL-XL inhibitors such as ABT-263 cannot be safely used in the clinic because platelets solely depend on BCL-XL to maintain their viability. To reduce the on-target platelet toxicity associated with the inhibition of BCL-XL, we designed and synthesized PROTAC BCL-XL degraders that recruit CRBN or VHL E3 ligase because both of these enzymes are poorly expressed in human platelets compared to various cancer cell lines. We confirmed that platelet-toxic BCL-XL/2 dual inhibitor ABT-263 can be converted into platelet-sparing CRBN/VHL-based BCL-XL specific degraders. A number of BCL-XL degraders are more potent in killing cancer cells than their parent compound ABT-263. Specifically, XZ739, a CRBN-dependent BCL-XL degrader, is 20-fold more potent than ABT-263 against MOLT-4 T-ALL cells and has >100-fold selectivity for MOLT-4 cells over human platelets. Our findings further demonstrated the utility of PROTAC technology to achieve tissue selectivity through recruiting differentially expressed E3 ligases.

Original languageEnglish (US)
Article number112186
JournalEuropean Journal of Medicinal Chemistry
Volume192
DOIs
StatePublished - Apr 15 2020
Externally publishedYes

Keywords

  • Apoptosis
  • BCL-X
  • Degradation
  • PROTAC
  • Platelet

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology
  • Organic Chemistry

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