I-138

I-138 is a potent, selective, and orally active allosteric inhibitor of the ubiquitin-specific protease 1 (USP1)-USP1-associated factor 1 (UAF1) complex with an IC50 of 4.1 nM. Originally developed by Forma Therapeutics, I-138 prevents the deubiquitination of proliferating cell nuclear antigen (PCNA) and FANCD2, leading to the accumulation of monoubiquitinated PCNA at replication forks, replication fork instability, and single-stranded DNA (ssDNA) gaps. This mechanism induces synthetic lethality in homologous recombination-deficient (HRD) tumors, particularly BRCA1-deficient breast and ovarian cancers. Preclinical studies have demonstrated that I-138 exhibits monotherapy activity and synergizes with PARP inhibitors (such as olaparib and niraparib) to overcome PARP inhibitor resistance in BRCA1-mutated cancer models.

Other names

2-(2-isopropylphenyl)-9-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,9-dihydro-8H-purin-8-oneI 138I138I-138USP1 inhibitor I-138USP-1 inhibitor I-138USP 1 inhibitor I-138