9n9y
From Proteopedia
Crystal structure of truncated USP1:UAF1 in complex with compound 18
Structural highlights
DiseaseWDR48_HUMAN Autosomal recessive spastic paraplegia type 60. FunctionWDR48_HUMAN Regulator of deubiquitinating complexes. Acts as a strong activator of USP1 by enhancing the USP1-mediated deubiquitination of FANCD2; USP1 being almost inactive by itself. Also activates deubiquitinating activity of complexes containing USP12 and USP46, respectively. Activates deubiquitination by increasing the catalytic turnover without increasing the affinity of deubiquitinating enzymes for the substrate. In case of infection by Herpesvirus saimiri, may play a role in vesicular transport or membrane fusion events necessary for transport to lysosomes. Induces lysosomal vesicle formation via interaction with Herpesvirus saimiri tyrosine kinase-interacting protein (TIP). Subsequently, TIP recruits tyrosine-protein kinase LCK, resulting in down-regulation of T-cell antigen receptor TCR. May play a role in generation of enlarged endosomal vesicles via interaction with TIP. In case of infection by papillomavirus HPV11, promotes the maintenance of the viral genome via its interaction with HPV11 helicase E1.[1] [2] [3] Publication Abstract from PubMedUSP1 (ubiquitin-specific peptidase 1) is a deubiquitinating enzyme that has been identified as essential in BRCA1/2 mutant cells and implicated in the DNA damage response. Inhibition of USP1 by small molecule inhibitors disrupts DNA repair and replication and is being pursued as a potential anticancer therapeutic in BRCA1/2 mutant cancers. We report the discovery of an in vitro and in vivo USP1 inhibitor tool compound TNG-6132 (18), a reversible, allosteric inhibitor of USP1, which strongly inhibits USP1 enzymatic activity. This inhibitory effect translates into in vitro cellular viability defects in a BRCA1-mutant breast cancer cell line, as well as an in vivo pharmacodynamic (PD) response and tumor growth suppression in a mouse xenograft efficacy model. Additionally, we report an X-ray co-crystal structure of TNG-6132 (18) bound in the USP1-UAF1 complex, a result that furthered our understanding of the role played by key elements of the pharmacophore of this chemotype as well as its mechanism of inhibition of USP1. Discovery of TNG-6132, a potent, selective, and orally bioavailable USP1 inhibitor.,Throner S, Feng T, Andersen JN, Bandi M, Engel JL, Gong S, Gotur D, Gu L, Huang A, Lazarides K, Maxwell JP, McCarren P, McMillan BJ, Pham TV, Simoneau A, Tsai A, Whittington DA, Wilker E, Zhang M, Zhang W Bioorg Med Chem Lett. 2025 Apr 30;124:130262. doi: 10.1016/j.bmcl.2025.130262. PMID:40315934[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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