ITRI-90
ITRI-90 is an orally active androgen receptor (AR) PROTAC degrader. ITRI-90 effectively degrades both full-length AR (AR-FL) and the splice variant AR-V7 protein via the ubiquitin-proteasome system, thereby inhibiting AR transcriptional activity and the target gene expression. ITRI-90 significantly inhibits the proliferation of prostate cancer cells and induces apoptosis, include Enzalutamide-resistant growth cell. ITRI-90 exhibits favorable pharmacokinetic properties and demonstrates potent antitumor efficacy in vivo. ITRI-90 can be used for prostate cancer research.
(Pink: Androgen Receptor ligand (HY-171809); Blue: VHL ligand (HY-125845A); Black: linker (HY-169966)).
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- CAS No.: 2798907-16-9
- Formule: C45H56F3N9O6S
- Masse moléculaire:908.04
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Stockage:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Activité biologique
ITRI-90 (0-20 μM,24 h) reduces AR-FL and AR-V(ΔLBD) proteins in LNCaP, CWR22Rv1, VCaP cells (with DC50 = 2.12, 5.73 and 8.67 nM for AR-FL proteins and DC50 = 4.72 and 0.29 nM for AR-V proteins in CWR22Rv1, VCaP cells respectively) [1].
ITRI-90 (10 μM, 24 h) demonstrates a prolonged duration of effect, enabling less frequent dosing in LNCaP, CWR22Rv1 and VCaP cells[1].
ITRI-90 (10 μM, 6 or 10 h) degrades AR protein levels via ubiquitin-proteasome dependent system in CWR22Rv1 and ITRI-126, cells[1].
ITRI-90 (0.1-1 μM,24 h) less efficiently inhibits AR target expression on both AR and AR-V7 signaling and exerts AR inhibition mediated via NTD-targeted protein degradation or direct blockade of ligand binding in LNCaP and CWR22Rv1 cells[1].
ITRI-90 (0.001-100 μM, 24 h or 7 days) specifically and effectively inhibits cancer cell proliferation and induces apoptosis in LNCaP, CWR22Rv1 and VCaP cells[1].
ITRI-90 (5 or 10 μM, one day ) effectively degrades Enzalutamide (HY-70002)-induced AR-FL and truncated AR V(ΔLBD) proteins in both short-term treated and long term acquired resistant cells, thereby significantly impairing the enzalutamide-resistant cell growth in VCaP, C4-2B and C4-2B/EnzR cells[1].
ITRI-90 shows low plasma clearance rate (6.62 mL/min/kg) and achieves well actual body exposure (AUC/Dose = 2502.4) in mouse liver microsomes[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:LNCaP, CWR22Rv1, VCaP cells
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Concentration:0, 0.01, 0.03, 0.1, 0.3, 1, 3, 10 and 20 μM
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Incubation Time:24 h
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Result:Effectively reduced AR-FL and AR-V(ΔLBD) proteins in a dose-dependent manner.
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Cell Line:LNCaP, CWR22Rv1, VCaP cells
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Concentration:10 μM
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Incubation Time:24 h
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Result:Displayed different kinetics of degradation and sustainability after drug washout at different time.
Achieved AR and AR-V(ΔLBD) degradation by 24 h treatment.
Appeared to sustain low pro tein levels up to 24 h after drug washout.
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Cell Line:CWR22Rv1 and 293T cells
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Concentration:10 μM
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Incubation Time:6 or 10 h
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Result:Degradation of AR and AR-V(ΔLBD) was recovered by MG132 and MLN4924 treatment.
Showed AR proteins strongly ubiquitinated.
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Cell Line:LNCaP, CWR22Rv1, VCaP cells
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Concentration:0.001, 0.01, 0.1, 1, 10 and 100 μM
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Incubation Time:7 days
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Result:Strongly inhibited cell growth by over 90% with IC50s = 6.587, 4.134, 5.454 μM for LNCaP, CWR22Rv1, VCaP cells, respectively.
Activated caspase 3/7 within 24 h.
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Cell Line:LNCaP and CWR22Rv1 cells
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Concentration:0.1 and 1μM
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Incubation Time:24 h
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Result:Decreased KLK3, NKX3.1 and TMPRSS2 expression in LNCaP and CWR22Rv1 cells.
Reduced CCNA2, CDC20, CDK1, UBE2C, UGT2B17 and EDN2 in CWR22Rv1 cells.
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Cell Line:LNCaP, CWR22Rv1, VCaP cells
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Concentration:0.001, 0.01, 0.1, 1, 10 and 100 μM
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Incubation Time:7 days
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Result:Strongly inhibited cell growth by over 90% for LNCaP, CWR22Rv1 and VCaP cells with IC50s = 6.587, 4.134 and 5.454 μM.
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Cell Line:LNCaP, CWR22Rv1, VCaP cells
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Concentration:10 μM
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Incubation Time:24 h
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Result:Rapidly activated caspase 3/7.
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Cell Line:VCaP, C4-2B/EnzR cells cells
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Concentration:10 μM
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Incubation Time:24 h
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Result:Reversed AR degraders significantly in VCaP cell.
Displayed Enzalutamide resistance as well as elevated AR-FL and AR-V7 in Long-term drug exposure of C4-2B Cells resulted in C4-2B/EnzR cells.
Efficiently reduced both AR-FL and the truncated AR-Vs.
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Cell Line:VCaP, EnzR cells
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Concentration:5 and 10 μM
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Incubation Time:24 h
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Result:Inhibits VCaP proliferation when combined with Enzalutamide.
Significantly inhibited EnzR cells proliferation.
| Species | Dose | Route | Tmax | Cmax |
|---|---|---|---|---|
| Mice[1] | 10 mg/kg | p.o. | 1.5 h | 3945 ng/mL |
ITRI-90 (100 mg/kg, p.o., twice daily for 21 days) is an orally available degrader specifically targeting AR-FL and LBD-truncated AR-Vs in tumor regression of the CWR22Rv1 xenograft mice model[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:CWR22Rv1 cells (5 × 106) induced-male C.B-17 SCID mice (4-6 weeks)[1]
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Dosage:10 mg/kg
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Administration:twice daily for 15 days
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Result:Significantly impaired the tumor growth without obvious toxicities[1].
Reached an average tumor growth inhibition (TGI) of 76.64% on day 12[1].
Significantly decreased AR-FL 12 and AR-V protein levels in tumors detected at the final time point[1].
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Animal Model:CWR22Rv1 cells (5 × 106) induced-male C.B-17 SCID mice (4-6 weeks)[1]
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Dosage:100 mg/kg
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Administration:p.o., twice daily for 21 days
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Result:Observed significant tumor suppression with an average TGI of 71.73 % without obvious toxicity[1].
Reduced protein levels of AR-FL and AR Vs in the tumors[1].
Chemical Information
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CAS No. 2798907-16-9
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Masse moléculaire 908.04
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Formule C45H56F3N9O6S
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SMILES
FC(F)(C1=NN=C2N1N=C(N3CCC(C4=CC=C(C=C4)OCCCCOCC(N[C@@H](C(C)(C)C)C(N5[C@@H](C[C@@H](C5)O)C(NCC6=CC=C(C7=C(N=CS7)C)C=C6)=O)=O)=O)CC3)CC2)F
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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.
Pureté et documentation
Références
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
ITRI-90 Related Classifications
HY-171808 Related Classifications
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