FR-027
FR-027 is an orally active, blood-brain barrier permeable XPO1 inhibitor with an EC50 value of 54-69 nM in human cells. FR-027 covalently modifies Cys528 of XPO1 via nucleophilic aromatic substitution, maintaining the nuclear export signal binding groove of XPO1 in a closed conformation to block the nuclear export process, and inhibits XPO1 function without inducing its protein degradation. FR-027 promotes cancer cell apoptosis and inhibits the growth of hematological and solid tumor cells. FR-027 can be used in research related to acute lymphoblastic leukemia, ovarian cancer, glioblastoma, and primary central nervous system lymphoma.
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- No. CAS: 3054389-11-3
- Fòrmula: C14H8F6N6O2
- Peso molecular:406.24
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Almacenamiento:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Descripciòn
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XPO1 54-69 nM (EC50) |
In Vitro
FR-027 (1-2.5 μM; 15 min preincubation) potently inhibits purified human XPO1 binding to the NES-containing GST-PKINES in vitro at concentrations of 1 μM and 2.5 μM[1].
FR-027 covalently modifies purified human XPO1 at residue Cys528 via nucleophilic aromatic substitution, forming a 122.9 Da nitro-imidazole adduct[1].
FR-027 does not induce XPO1 protein degradation in Jurkat, MOLT-4, U87-MG, OCI-LY7, or HAP1 human cancer cell lines[1].
FR-027 (1-2.5 μM) modified purified human XPO1 does not bind to purified GST-ASB8 in vitro at concentrations of 1 μM and 2.5 μM, due to the closed conformation of the XPO1 NES-binding groove[1].
FR-027 (33 μM; 1 h incubation) mediated inhibition of purified human XPO1 binding to GST-PKINES is reversible, with partial recovery after 24 hours in inhibitor-free buffer and enhanced reversal with DTT at pH 8.5[1].
FR-027 (2 h treatment; 24 h post-washout) mediated inhibition of XPO1-dependent nuclear export is reversible in HeLa reporter cells and wild-type Jurkat human T-ALL cells, with substantial recovery of cytoplasmic cargo localization 24 hours post-compound washout[1].
FR-027 (2 h) potently inhibits XPO1-mediated nuclear export in HeLa reporter cells with an EC50 of 54 nM[1].
FR-027 selectively targets XPO1 at Cys528 in Jurkat human T-ALL cells, as it fails to induce nuclear accumulation of endogenous RanBP1 in XPO1C528S mutant cells[1].
FR-027 reversibly inhibits XPO1 function with an EC50 of 69 nM without inducing XPO1 protein degradation[2].
FR-027 (0-10 μM; 72 h) potently inhibits proliferation of diverse human cancer cell lines with EC50 values of 0.04-0.28 μM, via selective targeting of XPO1 at Cys528[1].
FR-027 shows in vitro potency matching approved and second-generation XPO1 inhibitors in multiple tumor cell lines, including glioblastoma, and has distinct mechanistic properties: it binds XPO1 via a reversible covalent interaction and does not trigger proteasomal degradation of XPO1[3].
FR-027 enhances nuclear p53 localization and induces apoptosis in wild-type MOLT-4 human T-ALL cells via selective XPO1 inhibition, with no activity in XPO1C528S mutant cells[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:diverse panel of human cancer cell lines
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Concentration:0-10 μM
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Incubation Time:72 h
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Result:Reduced tumor cell viability across all tested cell lines with EC50 values ranging from 0.04 to 0.28 μM, matching the potency of selinexor and eltanexor.
Potently inhibited proliferation of wild-type cells but showed no activity in XPO1C528S mutant cells.
In Vivo
FR-027 (100 mg/kg; p.o.; three times per week; five weeks) delays ascites onset and extends median overall survival to 86 days in an immunocompetent C57BL/6 mouse model of advanced ovarian cancer[1].
FR-027 (100 mg/kg; p.o.; five times per week) significantly delays tumor growth and extends overall survival in both early and advanced orthotopic BALB/c nude mouse models of glioblastoma[1].
FR-027 (100 mg/kg; p.o.; five times per week) delays tumor progression, extends overall survival, and prevents intrathecal spinal metastasis in orthotopic BALB/c nude mouse models of PCNSL[1].
FR-027 (100 mg/kg; p.o.; five times per week; three weeks) demonstrates an improved hematologic safety profile in female CD-1 mice, with no suppression of platelet, lymphocyte, or neutrophil counts[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:NSG (NOD scid gamma) mice[1]
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Dosage:100 mg/kg
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Administration:p.o.; three times per week
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Result:Significantly delayed tumor growth as measured by bioluminescence imaging on day 23 after inoculation.
Extended overall survival compared with vehicle controls.
Prevented significant spleen enlargement (spleen size comparable to non-tumor-bearing mice).
Delayed the onset of paralysis due to CNS tumor involvement.
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Animal Model:C57BL/6 mice[1]
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Dosage:100 mg/kg
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Administration:p.o.; three times per week; five weeks
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Result:Delayed the onset of tumor-induced ascites and first ascites drainage.
Extended median overall survival to 86 days, compared with 58 days for vehicle controls and 73 days for standard-of-care platinum-based alkylating agent plus microtubule-stabilizing taxane treatment.
Was well tolerated with no significant weight loss.
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Animal Model:BALB/c nude mice[1]
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Dosage:100 mg/kg
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Administration:p.o.; five times per week
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Result:Significantly delayed tumor growth as measured by bioluminescence imaging and magnetic resonance imaging with early treatment, and extended overall survival compared with selinexor and eltanexor.
Substantially reduced tumor growth and nearly doubled median overall survival to 57 days with late treatment (initiated at day 19), compared with 29 days for vehicle controls.
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Animal Model:BALB/c nude mice[1]
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Dosage:100 mg/kg
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Administration:p.o.; five times per week
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Result:Delayed tumor progression, significantly extended overall survival compared with vehicle control, selinexor, and eltanexor, and prevented spinal metastasis (no increase in spinal tumor signal was observed, and the spinal-to-cranial tumor signal ratio was significantly lower than in vehicle controls by day 23) with early treatment.
Reduced tumor growth and prolonged survival relative to vehicle-treated animals with late treatment (initiated at day 19).
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Animal Model:CD-1 mice (female)[1]
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Dosage:100 mg/kg
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Administration:p.o.; five times per week; three weeks
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Result:Did not result in weight loss compared with vehicle controls.
Increased platelet counts by up to 24% relative to vehicle controls.
Modestly reduced red blood cell counts by 12%.
Left lymphocyte and neutrophil counts unchanged.
Chemical Information
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No. CAS 3054389-11-3
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Peso molecular 406.24
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Fòrmula C14H8F6N6O2
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SMILES
CN1C(N(C=N2)N=C2C3=CC(C(F)(F)F)=CC(C(F)(F)F)=C3)=C([N+]([O-])=O)N=C1
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Envío
Room temperature in continental US; may vary elsewhere.
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Almacenamiento
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureza y Documentación
Referencias
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
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