2. Cell Cycle/DNA Damage
  3. Deubiquitinase
  4. USP1-IN-15

USP1-IN-15 is an orally active and selective USP1 inhibitor with an IC50 of 12.3 nM. USP1-IN-15 has a high specificity for USP1 with negligible inhibition against all off-target DUBs. USP1-IN-15 suppresses colony formation, induces S-phase arrest, and stabilizes ubiquitinated PCNA. USP1-IN-15 also shows synergistic antiproliferative activity. USP1-IN-15 achieves significant tumor growth inhibition in vivo. USP1-IN-15 can be used for BRCA-mutated breast cancer.

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USP1-IN-15

USP1-IN-15 Chemical Structure

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USP1-IN-15 Related Antibodies

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USP1 USP2 USP4 USP7 USP8 USP10 USP21 USP30 UCHL1 USP11 USP15

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Description

USP1-IN-15 is an orally active and selective USP1 inhibitor with an IC50 of 12.3 nM. USP1-IN-15 has a high specificity for USP1 with negligible inhibition against all off-target DUBs. USP1-IN-15 suppresses colony formation, induces S-phase arrest, and stabilizes ubiquitinated PCNA. USP1-IN-15 also shows synergistic antiproliferative activity. USP1-IN-15 achieves significant tumor growth inhibition in vivo. USP1-IN-15 can be used for BRCA-mutated breast cancer[1].

IC50 & Target[1]

USP1

12.3 nM (IC50)

In Vitro

USP1-IN-15 (compound 43) (14 days) balances profile of potent antiproliferative activity with IC50 = 0.07 μM in MDA-MB-436 and good metabolic stability (t1/2 value exceeding 120 min) [1].
USP1-IN-15 (1 μM) has a high specificity for USP1 with negligible inhibition against all off-target DUBs (USP5, USP7, USP8, USP9X, USP14, USP15, USP25, USP28, BAP1, and OTUD1) [1].
USP1-IN-15 (0-1000 nM, 0-168 h) dose-and time-dependently potently and persistently inhibits the deubiquitination of proliferating cell nuclear antigen (PCNA) and induces protein level of p-H2AX in MDA-MB-436 breast cancer cells[1].
USP1-IN-15 (100-1000 nM, 48 h or 2-3 weeks) induces S-phase arrest in MDA-MB-436 breast cancer cells[1].
USP1-IN-15 (0.1-10 μM, 7 days or 2-3 weeks) dose dependently enhances growth inhibition compared to monotherapy when combined with Olaparib (HY-10162) in MDA-MB-436 cells[1].
USP1-IN-15 (1 μM, 48 h) has superior synergistic activity when combined with Olaparib through enhanced induction of DNA damage and cell cycle arrest in MDA-MB-436 cells[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

USP1-IN-15 Related Antibodies

Western Blot Analysis[1]

Cell Line: MDA-MB-436 cells
Concentration: 0.3, 1, 3, 10, 30, 100, 300 and 1000 nM
Incubation Time: 0, 6, 24, 48, 72, 96, 120, 144, and 168 h
Result: Exhibited deubiquitination inhibition, increased the protein level of ubiquitinated PCNA (ubPCNA) and induced the protein level of p-H2AX0 at 48 h and beyond in range of 0-168 h and 300 nM.
Increased the protein level of ubPCNA in a dose-dependent manner at lower concentrations (100 and 300 nM) .
Showed significantly higher ubPCNA levels at 100, 300, and 1000 nM.
Elevated p-H2AX protein levels at 100, 300, and 1000 nM.

Immunofluorescence[1]

Cell Line: MDA-MB-436 cells
Concentration: 300 nM
Incubation Time: 72 h
Result: Induced the superior p-H2AX signal intensity and more nuclear foci.

Cell Proliferation Assay[1]

Cell Line: MDA-MB-436 cells
Concentration: 100, 300, 1000 nM
Incubation Time: 2-3 weeks
Result: Inhibit the growth of clones in a dose-dependent manner.
Demonstrated superior antiproliferative activity, reducing colony counts by 55.99 % (300 nM) and 66.89% (1000 nM) .

Cell Cycle Analysis[1]

Cell Line: MDA-MB-436 cells
Concentration: 100, 300, 1000 nM
Incubation Time: 48 h
Result: Induced S-phase arrest at a concentration range of 100-1000 nM.

Cell Viability Assay[1]

Cell Line: MDA-MB-436 cells
Concentration: 0.1, 1, 10 μM
Incubation Time: 7 days
Result: Revealed stronger cell growth inhibition in combination regimens when combination with Olaparib.

Cell Cycle Analysis[1]

Cell Line: MDA-MB-436 cells
Concentration: 1 μM
Incubation Time: 48 h
Result: Induced significant cell cycle arrest with marked accumulation of cells in the S phase but induced significant accumulation of MDA-MB-436 cells at S and G2/M phases when combined with Olaparib.
Exhibited pronounced synergistic effects, resulting in a more robust cell cycle perturbation when combined with Olaparib.

Western Blot Analysis[1]

Cell Line: MDA-MB-436 cells
Concentration: 1 μM
Incubation Time: 48 h
Result: Elevated p-H2AX levels with or without combination with Olaparib but had a better effect when combinated with Olaparib.
Parmacokinetics
Species Dose Route Cmax AUC0-t AUC0-∞ T1/2 Tmax F
Mice[1] 1 mg/kg i.v. 1249 ng/mL 13161 ng·h/mL 13819 ng·h/mL 5.1 h / /
Mice[1] 10 mg/kg p.o. 3203 ng/mL 50767 ng·h/mL 93235 ng·h/mL 16.5 h 7 h 38.6 %
In Vivo

USP1-IN-15 (compound 43) (40 mg/kg, p.o., once daily, for 45 days) exhibits significant single-agent antitumor activity, produces a synergistic enhancement effect with Olaparib and indicates minimal systemic toxicity in a xenograft tumor mice model[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Model: MDA-MB-436 cells (5 × 106) induced-female nude mice(6-9 weeks, 17-19 g)[1]
Dosage: 40 mg/kg
Administration: p.o., once daily, for 45 days, with or without combination with Olaparib (30 mg/kg)
Result: Exhibited the most potent antitumor activity.
Exhibiting the most significant reduction (TGI = 82.734%) in tumor weight.
Observed no significant differences in body weight.
Demonstrated no statistically significant differences in organ indices of heart, liver, lung, and kidney.
Resulted significant reductions in Ki67-positive cells in both monotherapy or combination groups.
Elevated levels of ubPCNA in monotherapy.
Exhibited the highest level of p-H2AX, consistent with its robust DNA damage-inducing capability.
Molecular Weight

599.57

Formula

C30H24F3N9O2
SMILES

O=C1C2=NC=CN2C3=CN=C(N=C3N1CC4=CC=C(C=C4)N5N=C(C=C5C6CC6)C(F)(F)F)C7=C(N=CN=C7C8CC8)OC
Shipping

Room temperature in continental US; may vary elsewhere.
Storage

Please store the product under the recommended conditions in the Certificate of Analysis.
Purity & Documentation
References
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USP1-IN-15 Related Classifications

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Help & FAQs
  • Do most proteins show cross-species activity?

    Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.

Keywords:

USP1-IN-15DeubiquitinaseDUBsUSP1S-phase arrestubiquitinated PCNABRCA-mutated breast cancerInhibitorinhibitorinhibit

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