Optimization of Potent Ligands for the E3 Ligase DCAF15 and Evaluation of Their Use in Heterobifunctional Degraders

Unlocking
novel E3 ligases for use in heterobifunctional PROTAC
degraders is of high importance to the pharmaceutical industry. Over-reliance
on the current suite of ligands used to recruit E3 ligases could limit
the potential of their application. To address this, potent ligands
for DCAF15 were optimized using cryo-EM supported, structure-based
design to improve on micromolar starting points. A potent binder,
compound 24, was identified and subsequently conjugated
into PROTACs against multiple targets. Following attempts on degrading
a number of proteins using DCAF15 recruiting PROTACs, only degradation
of BRD4 was observed. Deconvolution of the mechanism of action showed
that this degradation was not mediated by DCAF15, thereby highlighting
both the challenges faced when trying to expand the toolbox of validated
E3 ligase ligands for use in PROTAC degraders and the pitfalls of
using BRD4 as a model substrate.