How long until someone uses these to degrade BRD4?!

ByeTAC: Bypassing E-Ligase-Targeting Chimeras for Direct Proteasome Degradation The development of targeted protein degradation by recruiting a protein of interest to a ubiquitin ligase to facilitate its degradation has become a powerful therapeutic tool. The potential of this ap...

While disease treatments often inhibit proteins, #PROTAC degrade them via ubiquitinase-protease recruitment. Darci Trader @ucirvine.bsky.social now show in J Med Cem proteases can be recruitet without ubiquitinases — a still less potent but interesting alternative.

pubs.acs.org/doi/10.1021/...

Very exciting @traderlab.bsky.social

ByeTAC: Bypassing E-Ligase-Targeting Chimeras for Direct Proteasome Degradation The development of targeted protein degradation by recruiting a protein of interest to a ubiquitin ligase to facilitate its degradation has become a powerful therapeutic tool. The potential of this approach is limited to proteins that can be readily ubiquitinated and relies on having a ligand with the various E3 ligases. Here, we describe a new methodology for targeted protein degradation that directly recruits a protein of interest to the proteasome for degradation. We generated bifunctional molecules that incorporate a small molecule ligand into a subunit on the 26S proteasome that recruits the protein directly for degradation. ByeTAC degradation requires binding to Rpn-13, a nonessential ubiquitin receptor of the 26S proteasome, and the protein of interest and does not have to rely on the E ligase cascade for ubiquitination. The ByeTAC methodology demonstrates the application of directly recruiting a protein to the proteasome via interactions with Rpn-13 for degradation.

ByeTACs is finally out in J. Med Chem. Congrats team! Can't wait to see how else we can use this degradation technology. @codyloy.bsky.social

pubs.acs.org/doi/10.1021/...

ByeTAC: Bypassing E-Ligase-Targeting Chimeras for Direct Proteasome Degradation The development of targeted protein degradation by recruiting a protein of interest to a ubiquitin ligase to facilitate its degradation has become a powerful therapeutic tool. The potential of this ap...

Beyond thrilled to finally have this paper out in J. Med. Chem. Check out @traderlab.bsky.social new targeted protein degradation mechanism, ByeTAC. 🧪🥼
doi.org/10.1021/acs....

Immunoproteasome as a Target for Prodrugs Immunoproteasome (iCP) is a proteasome isoform that is expressed under inflammatory conditions such as cytokine interferon-γ exposure. The iCP has different catalytic subunits other than the standard CP (standard core particle), allowing the production of major histocompatibility complex class I (MHC-I) compatible peptides for eventual T-cell activation. We have previously reported the design of a fluorescent probe that monitors iCP activity in cells called TBZ-1, and we applied TBZ-1’s iCP recognition sequence for prodrug release into iCP-active cells. Here, we demonstrate a proof-of-concept of the iCP as a prodrug release enzyme. The “payload” we utilized was a toxic moiety, doxorubicin, and a degrader for transcription factor, BRD4. Both examples show that iCP activity is required to elicit cell death or degradation of BRD4. This report highlights that the iCP is a viable prodrug target, and its activity can be used to release a variety of cargo in cells expressing the iCP.

Really proud to have this out in J Med Chem! Congrats to Christine and @codyloy.bsky.social
pubs.acs.org/doi/10.1021/...

Starting 2025 off with a review about degrons in @rscmedchem.bsky.social. Congrats Tim!

pubs.rsc.org/en/content/a...