Description
ML323 (1571424-83-5) is a potent and reversible USP1-UAF1 deubiquitinase complex inhibitor with excellent selectivity against human DUBs, deSUMOylase, deneddylase and unrelated proteases, IC50=76 nM in a ubiquitin-rhodamine 110 assay.1 In H1299 non-small cell lung cancer cells treatment with ML323 dose dependently and robustly increased levels of monoubiquitinated PCNA compared to untreated cells at concentrations as low as 1 μM.1 It potentiates cisplatin cytotoxicity in non-small cell lung cancer and osteosarcoma cells.2? ML323 inhibition of upregulated USP1 in BRCA1-deficient tumor cells results in replication fork destabilization and decreased viability.3
Uses
ML323 is a highly potent and selective USP1-UAF1 inhibitor.
in vitro
studies in h596 cells showed that ml-323 blocked the deubiquitination of pcna and fancd2 via suppressing usp1–uaf1 activity. it was reported that ml-323 potently inhibited usp1-uaf1 with ic50 values of 76 nm and 174 nm in ubiquitin-rhodamine (ub-rho) assay and orthogonal gel-based assay, respectively. in addition, by targeting tls and fa, two major dna damage response pathways, ml-323 increased cisplatin cytotoxicity both in nsclc h596 cells and u2os osteosarcoma cells. moreover, this agent exhibited a high selectivity to human dubs, desumoylase, deneddylase and unrelated proteases. [1]
IC 50
ml-323 is a highly potent and selective inhibitor of usp1-uaf1 with ic50 value of 76 nm.
References
1) Dexheimer et al. (2014), Synthesis and structure-activity relationship studies of N-benzyl-2-phenylpyrimidin-4-amine derivatives as potent USP1/UAF1 deubiquitinase inhibitors with anticancer activity against nonsmall cell lung cancer; J. Med. Chem., 57 8099
2) Liang et al. (2014), A selective USP1-UAF1 inhibitor links deubiquitination to DNA damage responses; Nat. Chem. Biol., 10 298
3) Lim et al. (2018) USP1 is required for replication fork protection in BRCA1-deficient tumors; Mol. Cell, 72 925
