Issue 8, 2021

Selective degradation-inducing probes for studying cereblon (CRBN) biology

Abstract

Targeted protein degradation represents a rapidly growing area in drug discovery and development. Moreover, small molecules that induce the targeted degradation of a given protein also represent an important addition to the chemical probes toolbox as these compounds can achieve selective protein knockdown, thus providing an approach that is orthogonal to genetic knockdowns. In order to develop degradation-inducing chemical probes for studying cereblon (CRBN) biology, we generated six CRBN–CRBN (homo-PROTAC) degraders and six CRBN–VHL (hetero-PROTAC) degraders. From these compounds we identified two potent and selective CRBN degraders (ZXH-4-130 and ZXH-4-137), both of which are CRBN–VHL compounds. We characterized these lead degraders by quantitative proteomics in five cell lines (MM1.S, Kelly, SK-N-DZ, HEK293T, and MOLT-4) and observed high selectivity for CRBN in all cell lines. Furthermore, we directly compared our compounds to current lead CRBN degraders and demonstrated how these probes can be used as chemical knockdown reagents for studying CRBN-dependent processes. Overall, our work provides a roadmap for thorough degrader characterization by combination western and proteomic analysis, as illustrated by the identification of ZXH-4-130 and ZXH-4-137 as CRBN-knockdown tool compounds suitable for cell-based studies.

Graphical abstract: Selective degradation-inducing probes for studying cereblon (CRBN) biology

Supplementary files

Article information

Article type
Research Article
Submitted
09 ное 2020
Accepted
15 мар 2021
First published
06 юли 2021

RSC Med. Chem., 2021,12, 1381-1390

Selective degradation-inducing probes for studying cereblon (CRBN) biology

C. E. Powell, G. Du, J. W. Bushman, Z. He, T. Zhang, E. S. Fischer and N. S. Gray, RSC Med. Chem., 2021, 12, 1381 DOI: 10.1039/D0MD00382D

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements