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.
Background
ML-323 is a small-molecule inhibitor of ubiquitin-specific protease 1, a deubiquitinase associated with the DNA damage response. USP1 and the WD repeat-containing protein form a deubiquitinase complex that removes ubiquitin from FANCD2, which is ubiquitinated in response to DNA damage. ML-323 is a potent and specific inhibitor of the USP1/UAF1 deubiquitinase complex. Dysregulation of USP1 is an aspect of several forms of cancer, making it a promising therapeutic target. ML-323 significantly repressed metastasis in a murine model of breast cancer and decreased hepatocellular carcinoma cell proliferation. Elevated USP1 expression in some colorectal cancers is associated with short overall patient survival and advanced stages of cancers. USP1 knockdown resulted in growth arrest at G2/M and reduced anti-apoptotic protein expression; ML-323 sensitized colorectal cancer cells to DNA-targeting chemotherapeutics. ML-323 treatment of non-small cell lung cancer and osteosarcoma cells potentiates the cytotoxic effects of cisplatin.
References
[1] THOMAS S. DEXHEIMER. 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]. Journal of Medicinal Chemistry, 2014, 57 19: 8099-8110. DOI:
10.1021/jm5010495[2] QIN LIANG. A selective USP1–UAF1 inhibitor links deubiquitination to DNA damage responses[J]. Nature chemical biology, 2014, 10 4: 298-304. DOI:
10.1038/nchembio.1455[3] KAH SUAN LIM. USP1 Is Required for Replication Fork Protection in BRCA1-Deficient Tumors.[J]. Molecular Cell, 2018, 72 6: 925-941.e4. DOI:
10.1016/j.molcel.2018.10.045
