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 interesting J. Med. Chem paper by the group of Darci Trader @traderlab.bsky.social. They developed ByeTACs to induce protein degradation by directly recruiting a POI to the proteasome subunit Rpn-13. They used this for E3-independent degradation of BRD4 and BTK. pubs.acs.org/doi/10....

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....

Giving kids liver damage to achieve nothing m, just to avoid a safe vaccine…the stupidity gets even stupider

www.latimes.com/california/story/2025-03...

There are days in life that shake you.

I’m shattered 💔 to share that I just found out that the US Government terminated my 2024 NIH Director’s Early Independence Award (~$2 million), threatening my long-promised assistant professor job at Columbia University
& academic career... 1/🧵

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/...

Synthesis and Application of a Versatile Immunoproteasome Activity Probe The ONX-0914-alkyne probe described here allows for the conjugation to a variety of fluorophores through click chemistry. It can then be used to visualize immunoproteasome activity in gel-based, micr....

New #ChemBioChem paper by the @traderlab.bsky.social:

"Synthesis and Application of a Versatile Immunoproteasome Activity Probe"

chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/...

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