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

Citations Over TimeTop 10% of 2020 papers

Abstract

Targeted protein degradation (TPD) and proteolysis-targeting chimeras (PROTACs) have arisen as powerful therapeutic modalities for degrading specific proteins in a proteasome-dependent manner. However, a major limitation of TPD is the lack of E3 ligase recruiters. Recently, we discovered the natural product nimbolide as a covalent recruiter for the E3 ligase RNF114. Here, we show the broader utility of nimbolide as an E3 ligase recruiter for TPD applications. We demonstrate that a PROTAC linking nimbolide to the kinase and BCR-ABL fusion oncogene inhibitor dasatinib, BT1, selectively degrades BCR-ABL over c-ABL in leukemia cancer cells, compared to previously reported cereblon or VHL-recruiting BCR-ABL degraders that show opposite selectivity or, in some cases, inactivity. Thus, we further establish nimbolide as an additional general E3 ligase recruiter for PROTACs, and we demonstrate the importance of expanding upon the arsenal of E3 ligase recruiters, as such molecules confer differing selectivity for the degradation of neo-substrate proteins.

Related Papers

• → Ubiquitination and Degradation of Mutant p53(2007)224 cited
• → Multiple E3 ligases act as antiviral factors against SARS-CoV-2 via inducing the ubiquitination and degradation of ORF9b(2024)17 cited
• → Promiscuous Interactions of gp78 E3 Ligase CUE Domain with Polyubiquitin Chains(2012)33 cited
• → The poxvirus encoded ubiquitin ligase, p28, is regulated by proteasomal degradation and autoubiquitination(2014)11 cited
• → Cereblon vs VHL: Hijacking E3 Ligases Against Each Other Using PROTACs(2019)