Structural basis for the bi-specificity of USP25 and USP28 inhibitors

ABSTRACT: The development of cancer therapeutics is often hindered by the fact that specific oncogenes cannot be directly pharmaceutically addressed. Targeting deubiquitylases which stabilize these oncogenes provides a promising alternative. USP28 and USP25 have been identified as such target deubiquitylases, and several small-molecule inhibitors indiscriminately inhibiting both enzymes have been identified. To obtain insights into their mode of inhibition, we structurally and functionally characterized USP28 in the presence of the three different inhibitors, AZ1, Vismodegib and FT206. The compounds bind into a common pocket acting as a molecular sink. Our analysis provides an explanation why the two enzymes are inhibited with similar potency, while other deubiquitylases are not affected. Furthermor

SUBMITTER: Prof. Caroline Kisker 

PROVIDER: S-SCDT-10_1038-S44319-024-00167-W | biostudies-other |

REPOSITORIES: biostudies-other