Schroeder, Martin (2024) Chimia column: DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance. Chimia; chemie report..

Abstract

Proteolysis Targeting Chimeras (PROTACs) revolutionize drug development by redirecting E3 ligases to ubiquitinate and degrade specific proteins. Curiously, the pivotal ligase CRBN is observed to decline in scenarios of resistance to immunomodulatory inhibitory drugs (IMiDs). This study explores the potential of utilizing the E3 ligase receptor DCAF1, employing a non-covalent DCAF1 binder transformed into a PROTAC E3 ligase anchor. Validation through chemical and genetic experiments confirms specific degradation via the CRL4 E3 ligase. This innovative strategy could provide an alternative to overcome predicted resistance against of CRBN-targeting PROTACS in clinical settings, shedding light on the promising prospect of leveraging DCAF1 for targeted protein degradation in drug development.
The here described DCAF1 ligands expand the spectrum of usable tool compounds to further investigate DCAF1 cellular functions and its potential as a ligase for TPD.

Item Type:	Article
Date Deposited:	29 Oct 2024 00:45
Last Modified:	29 Oct 2024 00:45
URI:	https://oak.novartis.com/id/eprint/53506