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

Xuan Zhang1, Dinesh Thummuri2, Xingui Liu2

  • 1Department of Medicinal Chemistry, College of Pharmacy, University of Florida, 1333 Center Drive, Gainesville, FL, 32610, United States.

European Journal of Medicinal Chemistry
|March 8, 2020
PubMed

Insights

Researchers developed novel PROTAC BCL-XL degraders to target cancer cells while sparing platelets. These degraders offer a safer approach to cancer therapy by exploiting differences in E3 ligase expression between cancer cells and platelets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Anti-apoptotic protein BCL-XL is crucial in cancer development and treatment resistance.
  • Existing BCL-XL inhibitors like ABT-263 cause significant platelet toxicity due to platelets' reliance on BCL-XL.

Purpose of the Study:

  • To design and synthesize Proteolysis-Targeting Chimeras (PROTACs) that selectively degrade BCL-XL in cancer cells.
  • To reduce on-target platelet toxicity by leveraging differential E3 ligase expression.

Main Methods:

  • Designed and synthesized PROTAC BCL-XL degraders recruiting CRBN or VHL E3 ligases.
  • Assessed the potency and selectivity of degraders against cancer cell lines and human platelets.
  • Compared the efficacy of degraders to the parent compound ABT-263.

Main Results:

  • PROTAC BCL-XL degraders were successfully developed, converting platelet-toxic inhibitors into platelet-sparing agents.
  • Several degraders demonstrated enhanced potency against cancer cells compared to ABT-263.
  • XZ739, a CRBN-dependent degrader, showed 20-fold greater potency against MOLT-4 T-ALL cells and >100-fold selectivity over human platelets.

Conclusions:

  • PROTAC technology can achieve tissue selectivity by recruiting differentially expressed E3 ligases.
  • This approach offers a promising strategy for developing safer and more effective cancer therapeutics targeting BCL-XL.
Keywords:
ApoptosisBCL-X(L)DegradationPROTACPlatelet

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