Language

English

Publication Date

12-5-2024

Journal

European Journal of Medicinal Chemistry

DOI

10.1016/j.ejmech.2024.116904

PMID

39341093

PMCID

PMC11960843

PubMedCentral® Posted Date

4-1-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Chemically induced proximity modalities such as targeted protein degradation (TPD) hold promise for expanding the number of proteins that can be manipulated pharmacologically. However, current TPD strategies are often limited to proteins with preexisting ligands. Molecular glues (e.g. glutarimide ligands for CUL4CRBN), offer the potential to target undruggable proteins. Yet, their rational design is largely unattainable due to the unpredictability of the ‘gain-of-function’ nature of the glue interaction upon chemical modification of ligands. We recently reported a covalent trans-labelling glue mechanism which we named ‘Template-assisted covalent modification’, where an electrophile decorated BRD4 inhibitor was effectively delivered to a cysteine residue on DCAF16 due to an electrophile-induced BRD4-DCAF16 interaction. Herein, we report our efforts to evaluate how various electrophilic modifications to the BRD4 binder, JQ1, affect DCAF16 recruitment and subsequent BRD4 degradation efficiency. We discovered a moderate correlation between the electrophile-induced BRD4-DCAF16 ternary complex formation and BRD4 degradation. Moreover, we show that a more solvent-exposed warhead presentation optimally recruits DCAF16 and promotes BRD4 degradation. The diversity of covalent attachments in this class of BRD4 degraders suggests a high tolerance and tunability for the BRD4-DCAF16 interaction. This offers a new avenue for rational glue design by introducing covalent warheads to known binders.

Keywords

Transcription Factors, Cell Cycle Proteins, Humans, Proteolysis, Molecular Structure, Triazoles, Structure-Activity Relationship, Azepines, Dose-Response Relationship, Drug, Bromodomain Containing Proteins

Published Open-Access

yes

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