USP1-IN-20
USP1-IN-20 is an orally effective and selective USP1 inhibitor with an IC50 of 3.0 nM. USP1-IN-20 inhibits the USP1-UAF1 complex, leading to the accumulation of Ub-PCNA, which in turn induces DNA damage and G2/M phase arrest, while simultaneously promoting the degradation of the oncogenic protein c-MYC. USP1-IN-20 can be used for research on breast cancer and diffuse large B-cell lymphoma.
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- CAS No.: 3094127-54-2
- Formule: C28H25F3N6O
- Masse moléculaire:518.53
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Stockage:
Please store the product under the recommended conditions in the Certificate of Analysis.
To place orders, for customer services and technical support, please contact: MedChemExpress USA
Tel: 609-228-6898 E-mail: [email protected] [email protected]
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Activité biologique
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Chemical Information
- Protocole
- Pureté et documentation
- Références
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Activité biologique
Description
IC50 & Target
[1]|
USP1 3.0 nM (IC50) |
Cellular Effect
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Cell Line
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Type | Value | Description | References |
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| MDA-MB-436 | GI50 |
16.2 nM
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Antiproliferative activity against BRCA1-mutant triple-negative breast cancer MDA-MB-436 cells assessed as inhibition of cell growth.
Antiproliferative activity against BRCA1-mutant triple-negative breast cancer MDA-MB-436 cells assessed as inhibition of cell growth.
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acs.jmedchem.6c01009 |
| MDA-MB-436 | IC50 |
11.5 nM
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Inhibition of colony formation in BRCA1-deficient MDA-MB-436 cells.
Inhibition of colony formation in BRCA1-deficient MDA-MB-436 cells.
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acs.jmedchem.6c01009 |
In Vitro
USP1-IN-20 (compound 38 a) (7 days) selectively inhibits the proliferation of BRCA-deficient cancer cells, especially MDA-MB-436 cells, with a GI50 of 16.2 nM, while having little effect on BRCA wild-type and normal cells[1].
USP1-IN-20 (10 nM-10 μM; 10 days) exhibits significant colony formation inhibitory activity in MDA-MB-436 cells with an IC50 of 11.5 nM[1].
USP1-IN-20 (30 nM-1 μM; 24 h) induces G2/M cell cycle arrest, causes significant accumulation of Ub-PCNA and γ-H2AX protein levels, and leads to downregulation of c-MYC protein levels in MDA-MB-436 cells[1].
USP1-IN-20 (15 min) exhibits extremely potent USP1-UAF1 inhibitory activity in the USP1 enzymatic assay, with an IC50 of 3.0 nM[1].
USP1-IN-20 (1 μM) showed weak inhibition of Src kinase in a 120-kinase selectivity screen, with no significant activity against other kinases[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only. Further protocols information, click here.
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Cell Line:MDA-MB-436 cells
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Concentration:30, 300, 1000 nM
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Incubation Time:24 h
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Result:Dose-dependently induced significant G2/M phase cell cycle arrest (arrest rate increased from 19.4% to 34.3%).
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Cell Line:MDA-MB-436 cells
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Concentration:30, 100, 300, 1000 nM
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Incubation Time:24 h
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Result:Induced a dose-dependent accumulation of Ub-PCNA and the DNA damage marker γ-H2AX, and significantly down-regulated c-MYC protein levels.
Parmacokinetics
In Vivo
USP1-IN-20 (100 mg/kg; oral administration; once daily; 27 days) significantly inhibited tumor growth in a DLBCL-derived xenograft NOD-SCID mouse model with high c-MYC expression and TP53 mutation, with efficacy comparable to the first-line standard therapy R-CHOP[1].
USP1-IN-20 (100-300 mg/kg; oral administration; once daily; 4 weeks) had mild and reversible immunomodulatory side effects and abnormal liver enzyme effects in normal BALB/c mice, without long-term irreversible organ structural damage[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:NOD-SCID mice[1]
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Dosage:50 mg/kg, 100 mg/kg
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Administration:p.o.; once daily; 34 days
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Result:Induced dose-dependent tumor growth inhibition with TGI rates of 4.5% at 50 mg/kg and 33.6% at 100 mg/kg.
Upregulated Ub-PCNA, significantly elevated P27 and P21 levels, and accumulated γ-H2AX in all treated groups.
Induced no significant body weight loss.
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Animal Model:NOD-SCID mice[1]
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Dosage:100 mg/kg
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Administration:p.o.; once daily; 27 days
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Result:Suppressed tumor growth with a TGI rate of 64.7%.
Maintained stable or increased body weight over the treatment period.
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Animal Model:Mice[1]
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Dosage:100 mg/kg, 300 mg/kg
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Administration:p.o.; once daily; 4 weeks
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Result:Induced no significant changes in body weight at both doses.
Induced significant abnormalities in hepatic function markers (ALP, ALT, AST) after 4 weeks, which mostly normalized within 2 weeks of dosing cessation.
Revealed no overt structural damage to the liver or other organs via H&E staining.
Chemical Information
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CAS No. 3094127-54-2
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Masse moléculaire 518.53
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Formule C28H25F3N6O
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SMILES
CN1C(C2=CC=C(CN3C4=CC(C5=C(N=CN=C5OC)C6CC6)=NC(C)=C4C=C3)C=C2)=NC(C(F)(F)F)=C1
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Livraison
Room temperature in continental US; may vary elsewhere.
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Stockage
Please store the product under the recommended conditions in the Certificate of Analysis.
Protocole
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Cell Cytotoxicity Assay
Cytotoxicity assays are usually based on the assessment of cell membrane damage, which can also be indirectly detected by measuring cell viability. Detection methods include MTT assay, CKK-8 assay, LDH assay and ATP assay, etc.
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PCNA Immunodetection Proliferation Assay
PCNA immunodetection measures proliferative activity by detecting proliferating cell nuclear antigen, a nuclear protein associated with DNA polymerase δ function and DNA replication. The assay readout is the proportion of PCNA-positive nuclei among total counted cells, but PCNA labeling is not identical to BrdU labeling because PCNA can mark late G1/early S-associated replication competence and may persist beyond active DNA synthesis depending on fixation and extraction conditions.
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Flow cytometric DNA-content cell-cycle staining
Flow cytometric DNA-content cell-cycle staining measures the fluorescence intensity of DNA-bound fluorochromes in single cells or nuclei to estimate DNA content distributions, allowing assignment of populations to G0/G1, S, and G2/M phases by DNA histogram deconvolution. Propidium iodide (PI) intercalates into DNA, and PI fluorescence is proportional to cellular DNA content when staining is performed under conditions that make DNA accessible and minimize non-DNA signal. Cells with G2/M DNA content are expected to show approximately twice the fluorescence intensity of G0/G1 cells, while S-phase cells occupy intermediate fluorescence values. PI-based DNA-content analysis can also detect cells with fractional DNA content, often reported as sub-G1, when DNA fragmentation and extraction during staining reduce retained DNA signal in apoptotic cells. DAPI is an alternative DNA fluorochrome for univariate DNA-content analysis, while bivariate approaches combining DNA content with proliferation
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Protocol for Cell Cycle
Cell-cycle analysis by flow cytometry measures DNA content in single cells to estimate the fraction of cells in G0/G1, S, and G2/M phases. Propidium iodide intercalates into DNA, and after RNA removal with RNase, fluorescence intensity reflects cellular DNA content: 2N cells are assigned to G0/G1, cells between 2N and 4N to S phase, and 4N cells to G2/M. DNA-content analysis alone cannot reliably separate G0 from G1 or G2 from M. Ki-67 can distinguish quiescent G0 cells from cycling cells, EdU or BrdU incorporation marks active DNA synthesis in S phase, and phospho-histone H3 staining identifies mitotic cells within the 4N population.
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Breast Cancer Modeling
Breast cancer is a heterogeneous cancer, and it has been distinguished into four subtypes: luminal A, luminal B, HER2-positive and basal-like. Molecular mutations, epigenetic alterations, hormone exposure and immune microenvironment are related to the progression of breast cancer.
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Genotoxicity/Mutagenicity Study
The bacterial reverse mutation assay detects point mutations that restore amino-acid prototrophy in auxotrophic Salmonella typhimurium or Escherichia coli tester strains; after exposure to a test article, mutagenic activity is read out as an increased number of revertant colonies on minimal agar compared with the vehicle control. The assay uses tester strains with different mutation targets so that base-substitution and frameshift mutagens can be detected, and testing is performed with and without exogenous mammalian metabolic activation because some chemicals require biotransformation to become mutagenic.
Pureté et documentation
Références
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
USP1-IN-20 Related Classifications
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