Chemical Proteomics Identifies RBBP7 as a New E3 Ligase Supporting Targeted Protein Degradation

By incorporating the ynamide covalent warhead into the solvent-exposed piperidine ring of ibrutinib, we developed degraders that effectively induce BTK degradation through recruitment of E3 ubiquitin ligase RBBP7. Moreover, the ynamide motif serves as a transplantable chemical handle for the development of various small molecule degraders. These findings establish a rational design strategy for constructing potent degraders.

Abstract

Targeted protein degradation (TPD) has been recognized as a powerful therapeutic strategy for the treatment of a wide range of diseases. However, the application of existing degraders is constrained by their dependence on a limited number of E3 ubiquitin ligases, such as CRBN and VHL. To address this limitation, we developed a suite of novel small-molecule degraders by integrating an ynamide electrophile into protein-targeting ligands. These compounds demonstrated remarkable target degradation capability. Subsequent proteome profiling and functional validation revealed that Cys97 residue of retinoblastoma binding protein 7 (RBBP7) E3 ligase was covalently engaged and responsible for the degradation mechanism. Furthermore, the ynamide motif has proved to be a versatile and transplantable chemical handle, facilitating the development of degraders targeting a wide range of proteins, including CDK4, PDE5, PI3K, AKT, BCR-ABL, BRD4, EGFR^L858R, and EGFR^{L858R/T790M/C797S}. Notably, incorporation of ynamide into the “pan-kinase” inhibitor XO44 yielded degraders capable of simultaneously degrading various kinases, such as PI3K, Syk, AKT, and GSK-3β, further highlighting the general feasibility of this approach. Importantly, the ynamide-containing degraders demonstrated significantly enhanced anticancer potency compared to their parent inhibitors.

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