Abstract 4441: Discovery of potent and selective inhibitors of USP7 with anti-tumor activity in vitro and in vivo

Ohol, Yamini M.; Sun, Michael; Leger, Paul; Hu, Dennis X.; Biannic, Bérenger; Rana, Payal; Cho, Cynthia; Jacobson, Scott; Wong, Steve; Sanchez, Jerick; Han, Xinping; Young, Kyle P. De; Okano, Akinori; Maung, Jack; Cutler, Gene; Shah, Niket; Adusumilli, Lavanya; Kaveri, Deepika; Talay, Oezcan; Pookot, Deepa; Abraham, Betty; Bradford, Delia; Kozon, Nathan; Colas, Christophe; Kim, Andrea; Schwarz, Jacob B.; Wustrow, David; Brockstedt, Dirk G.; Kassner, Paul D.

doi:10.1158/1538-7445.sabcs18-4441

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“…Therefore, the structural information extracted from the reported high‐resolution structures of USPs in either apo or ligand‐bound state is very valuable for a deeper understanding of the interacting mode between Vismodegib and USP28. As it has been well known, quite a few of DUB members such as USP7 and USP14 have attracted much attention due to their potential as therapeutic targets for cancer therapy, and multiple active compounds targeting these DUBs have been developed [26,27,29,58–62]. We then thoroughly analyzed the reported crystal structures of USP7 complexed with its inhibitors and found that all of these compounds would selectively bind to one of the two binding cavities in USP7's catalytic domain (Fig.…”

Section: Discussionmentioning

confidence: 99%

USP28 and USP25 are downregulated by Vismodegib in vitro and in colorectal cancer cell lines

et al. 2020

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Deubiquitinase USP28 plays a crucial role in tumorigenesis by enhancing the stabilities of multiple cancer‐related proteins including c‐Myc, Notch1, and LSD1, and has become an attractive target for anticancer drug development. However, to date, only a few of USP28‐targeted active compounds have been developed, and the active compound‐binding pocket in USP28 has not been experimentally revealed yet. In this study, bioassay‐based high‐throughput screening was applied to discover USP28‐targeted inhibitors from the commercially available drug library. Vismodegib, an inhibitor of Hedgehog signaling pathway and FDA‐approved drug for the treatment of basal cell carcinoma, was found to exhibit inhibition activity against USP28 (IC50: 4.41 ± 1.08 μm). Multiple biophysical and biochemical techniques including NMR, ITC, thermal shift assay, HDX‐MS, and site‐directed mutagenesis analysis were then used to characterize the interaction between Vismodegib and USP28. The binding pocket in USP28 for Vismodegib, which is mainly composed of two helical structures spanning D255‐N278 and N286‐Y293, was revealed. According to the possible binding pose generated by HDX‐MS data‐defined molecular docking, the binding cavity occupied by Vismodegib in USP28 aligns well with one of the reported‐binding pockets in USP7 for its inhibitors. Furthermore, cellular assays were conducted to confirm that Vismodegib could interact with the evolutionarily related deubiquitinases USP28 and USP25 and downregulate the levels of the two enzymes' substrate proteins c‐Myc, Notch1, and Tankyrase‐1/2.

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Section: Discussionmentioning

confidence: 99%