Maintaining cell health by targeted protein degradation

Division Of Basic Sciences - Nci

Investigators

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Abstract

We have generated improved hRpn13-targeting small molecules that are being tested for restriction of tumor growth in mouse xenograft studies of multiple myeloma and various solid tumors. We optimized XL5-based PROTACs and found molecular dynamics (MD) simulations on model structures of hRpn13:PROTAC:VHL to be moderately predictive of efficacy. We also discovered a class of hRpn13 glue-like degrader compounds that are being further optimized and tested for efficacy in preventing tumor growth. We made the important discovery that proteasome constituency and regulation varies by cell and tissue type and that hRpn13 contributes to this specialization of proteasomes. Specifically, it binds to the bone marrow-specific arginine deiminase PADI4, including at proteasomes, the activity of which is inhibited by PAD4 inhibition. Our studies indicate that hRpn13 acts dually in protein degradation and expression, with its role in expression imparted partially by its interaction with histone deacetylase HDAC8.