Thread by @RPNowak

Pleased to share our story on Structure-Guided Design of a “Bump-and-Hole” Bromodomain-Based #Degradation Tag: BRD4-BD1-L94V #BromoTAG
We combine it with #dTAG to show simultaneous protein depletion!
@DrXiongY @kdonovan1008 @Nicky_eleuteri @fischerlab1
pubs.acs.org/doi/10.1021/ac…

XY-06-007 is a structure based designed CRBN degrader, which binds to BRD4 BD1 L94V and has limited affinity to BRD4 BD1.

Reduced binding to BRD4 BD1 translates to selective degradation of the L94V mutant in a GFP-fusion mCherry reporter line.

and exquisite proteome wide selectivity. One of the few cases where no degradation is the optimal outcome!

We further combine dTAG and #BromoTAG tag in a single cell line to demonstrate simultaneous degradation of two targets.

Interestingly, co-treatment of two CRBN based degraders has no impact on degradation of individual tagged proteins.

But combining VHL-based dTAG-V1 with CRBN-based XY-06-007 resulted in deeper degradation of the #BromoTAG, but not the #dTAG.

We hypothesize this could be a result of PGP (MDR1) inhibition by the #PROTAC, and indeed similar result can be observed with a PGP inhibitor.

We hope that combinations of #BromoTAG will enable further studies into synergies of protein depletion and we are very excited to share it! Feel free to reach out if you would like to test it!

Thank you @ACSBioMed! Go degradation!