9N9Y

Crystal structure of truncated USP1:UAF1 in complex with compound 18

This is a non-PDB format compatible entry.

Summary for 9N9Y

• Entry DOI: 10.2210/pdb9n9y/pdb
• Descriptor: WD repeat-containing protein 48, Ubiquitin carboxyl-terminal hydrolase 1, N-terminal fragment,Ubiquitin carboxyl-terminal hydrolase 1, ZINC ION, ... (5 entities in total)
• Functional Keywords: ubiquitin, cysteine protease, allosteric inhibitor, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 107544.83

Authors

Whittington, D.A. (deposition date: 2025-02-11, release date: 2025-05-14, Last modification date: 2025-05-21)

Primary citation

Throner, S.,Feng, T.,Andersen, J.N.,Bandi, M.,Engel, J.L.,Gong, S.,Gotur, D.,Gu, L.,Huang, A.,Lazarides, K.,Maxwell, J.P.,McCarren, P.,McMillan, B.J.,Pham, T.V.,Simoneau, A.,Tsai, A.,Whittington, D.A.,Wilker, E.,Zhang, M.,Zhang, W.
Discovery of TNG-6132, a potent, selective, and orally bioavailable USP1 inhibitor.
Bioorg.Med.Chem.Lett., 124:130262-130262, 2025

PubMed Abstract: USP1 (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.

PubMed: 40315934
DOI: 10.1016/j.bmcl.2025.130262

Experimental method

X-RAY DIFFRACTION (3.15 Å)