2. Academic Validation
  3. Discovery of PROTAC BCL-XL degraders as potent anticancer agents with low on-target platelet toxicity

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

  • Eur J Med Chem. 2020 Apr 15;192:112186. doi: 10.1016/j.ejmech.2020.112186.
Xuan Zhang 1,  Dinesh Thummuri 2,  Xingui Liu 2,  Wanyi Hu 1,  Peiyi Zhang 1,  Sajid Khan 2,  Yaxia Yuan 2,  Daohong Zhou 3,  Guangrong Zheng 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, College of Pharmacy, University of Florida, 1333 Center Drive, Gainesville, FL, 32610, United States.
  • 2 Department of Pharmacodynamics, College of Pharmacy, University of Florida, 1333 Center Drive, Gainesville, FL, 32610, United States.
  • 3 Department of Pharmacodynamics, College of Pharmacy, University of Florida, 1333 Center Drive, Gainesville, FL, 32610, United States. Electronic address: [email protected].
  • 4 Department of Medicinal Chemistry, College of Pharmacy, University of Florida, 1333 Center Drive, Gainesville, FL, 32610, United States. Electronic address: [email protected].
PMID: 32145645 DOI: 10.1016/j.ejmech.2020.112186
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.

Keywords

Apoptosis; BCL-X(L); Degradation; PROTAC; Platelet.

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