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Chemoproteomics-enabled discovery of covalent RNF114-based degraders that mimic natural product function.

Abstract：

:The translation of functionally active natural products into fully synthetic small-molecule mimetics has remained an important process in medicinal chemistry. We recently discovered that the terpene natural product nimbolide can be utilized as a covalent recruiter of the E3 ubiquitin ligase RNF114 for use in targeted protein degradation-a powerful therapeutic modality within modern-day drug discovery. Using activity-based protein profiling-enabled covalent ligand-screening approaches, here we report the discovery of fully synthetic RNF114-based recruiter molecules that can also be exploited for PROTAC applications, and demonstrate their utility in degrading therapeutically relevant targets, such as BRD4 and BCR-ABL, in cells. The identification of simple and easily manipulated drug-like scaffolds that can mimic the function of a complex natural product is beneficial in further expanding the toolbox of E3 ligase recruiters, an area of great importance in drug discovery and chemical biology.

journal_name

Cell Chem Biol

journal_title

Cell chemical biology

authors

Luo M,Spradlin JN,Boike L,Tong B,Brittain SM,McKenna JM,Tallarico JA,Schirle M,Maimone TJ,Nomura DK

doi

10.1016/j.chembiol.2021.01.005

subject

Has Abstract

pub_date

2021-01-22 00:00:00

eissn

2451-9456

issn

2451-9448

pii

S2451-9456(21)00005-2

pub_type

杂志文章

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