P53 upregulation by USP7-engaging molecular glues

Abstract

Molecular glues are typically small chemical molecules that act on the interface between the target protein and the degradation machinery to trigger ternary complex formation. Identification of molecular glues is challenging, and there has been a lack of target-upregulating molecular glues, which are desired for many targets such as tumor suppressor proteins (TSPs). TSPs are usually degraded by the proteasome through polyubiquitination (poly-ub) by specific E3 ligases, whereas deubiquitinases (DUBs) are capable of removing poly-ub conjugates to counteract these E3 ligases. Thus, small molecular glues that enhance the anchoring of TSPs to DUBs may stabilize them through deubiquitination. Here, through small-molecule microarray-based technology and unbiased screening, we identified three potential molecular glues that may tether P53 to the DUB USP7 and elevate the P53 level. Among them, bromocriptine (BC) is an FDA-approved drug showing the most robust effects. We further demonstrated that BC increased P53 stability via the predicted molecular glue mechanism engaging USP7. To confirm the generality of the screening platform, we identified another USP7-engaging molecular glue that upregulates PTEN, which is another well-known TSP. Taken together, we established a potential screening platform that may facilitate the discovery of novel molecular glues stabilizing TSPs via engaging the DUB USP7. Similar strategies could be applied to the identification of other types of molecular glues that may benefit drug discovery and chemical biology studies.