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A Nimbolide-Based Kinase Degrader Preferentially Degrades Oncogenic BCR-ABL

Bingqi Tong1,2, Jessica N Spradlin1,2, Luiz F T Novaes1,2

  • 1Department of Chemistry, University of California, Berkeley, Berkeley, California 94720, United States.

ACS Chemical Biology
|June 23, 2020
PubMed

Insights

Nimbolide, a natural product, is a new E3 ligase recruiter for targeted protein degradation (TPD). PROTACs using nimbolide selectively degrade BCR-ABL in leukemia cells, expanding TPD therapeutic options.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Targeted protein degradation (TPD) and proteolysis-targeting chimeras (PROTACs) offer novel therapeutic strategies by degrading specific proteins.
  • A key limitation in TPD is the scarcity of effective E3 ligase recruiters.
  • Nimbolide, a natural product, was recently identified as a covalent RNF114 E3 ligase recruiter.

Purpose of the Study:

  • To investigate the broader utility of nimbolide as an E3 ligase recruiter for TPD applications.
  • To develop and evaluate a novel PROTAC incorporating nimbolide for targeted protein degradation.
  • To assess the selectivity and efficacy of nimbolide-based PROTACs in cancer cells.

Main Methods:

  • Synthesis of a PROTAC (BT1) linking nimbolide to dasatinib, a BCR-ABL inhibitor.
  • Evaluation of BT1's ability to induce selective degradation of BCR-ABL in leukemia cancer cells.
  • Comparison of nimbolide-recruiting PROTAC selectivity with existing cereblon and VHL-recruiting PROTACs.

Main Results:

  • Nimbolide effectively functions as a general E3 ligase recruiter for TPD.
  • The nimbolide-dasatinib PROTAC (BT1) selectively degraded BCR-ABL over c-ABL in leukemia cells.
  • This selectivity differs from previously reported BCR-ABL degraders, highlighting the impact of E3 ligase choice.

Conclusions:

  • Nimbolide represents a valuable addition to the toolkit of E3 ligase recruiters for PROTAC development.
  • The choice of E3 ligase recruiter significantly influences the selectivity profile of PROTACs for neo-substrate degradation.
  • Expanding the repertoire of E3 ligase recruiters is crucial for advancing TPD therapeutics.

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