2. PROTAC NF-κB
  3. Molecular Glues Keap1-Nrf2
  4. VVD 065

VVD 065 is an orally active KEAP1-dependent NRF2 molecular glue degrader with a KEAP1 KD of 65 nM. VVD 065 covalently engages KEAP1 at Cys151, allosterically stabilizes KEAP1-CUL3 complex formation and enhances NRF2 polyubiquitination and proteasomal degradation. VVD 065 can be used for the research of esophageal squamous cell carcinoma, lung cancer, head-and-neck cancer, uterine cancers.

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VVD 065

VVD 065 Chemical Structure

CAS No. : 3034876-85-9

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VVD 065 Related Antibodies

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Description

VVD 065 is an orally active KEAP1-dependent NRF2 molecular glue degrader with a KEAP1 KD of 65 nM. VVD 065 covalently engages KEAP1 at Cys151, allosterically stabilizes KEAP1-CUL3 complex formation and enhances NRF2 polyubiquitination and proteasomal degradation. VVD 065 can be used for the research of esophageal squamous cell carcinoma, lung cancer, head-and-neck cancer, uterine cancers[1][2][3].

In Vitro

VVD 065 potently reduces NRF2 protein levels in wild-type KEAP1/NRF2, KEAP1-mutant, and NRF2-mutant cellular settings, inhibits NRF2-dependent gene expression, and suppresses proliferation of NRF2-dependent cancer cell lines at low nM concentrations[2].

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

VVD 065 Related Antibodies
In Vivo

VVD-065 (0.3-50 mg/kg; p.o.; QD or BID) induces robust NRF2 degradation and tumor growth inhibition in KYSE70 xenograft mice[3].
VVD-065 (2-50 mg/kg; p.o.; QD or BID) produces potent, sustained tumor growth inhibition in HCC95 xenograft mice[3].
VVD-065 (50 mg/kg; p.o.; QD or BID) drives tumor growth inhibition in diverse PDX models[3].
VVD-065 (50 mg/kg; p.o.; QD) improves overall survival and reduces tumor burden in orthotopic KLN-205 syngeneic mice[3].

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

Animal Model: NSG mice (inoculated 5 × 106 KYSE70 cells subcutaneously into the dorsal flank)[3]
Dosage: 5 mg/kg; 25 mg/kg; 50 mg/kg
Administration: p.o.; QD or BID
Result: Showed dose-dependent plasma exposure and intratumoral KEAP1_Cys151 target engagement.
Induced robust NRF2 protein degradation and reduced expression of NRF2 target genes (AKR1B10, AKR1C1, CYP4F11, NR0B1, SLC7A11) by >50% relative to vehicle at 5 mg/kg QD.
Achieved robust tumor growth inhibition (TGI) with significant suppression of tumor volume compared to vehicle control (P ≤ 0.0001) across all tested doses.
Achieved maximal KEAP1_Cys151 engagement shortly after single 5 mg/kg QD dosing, with engagement declining over 72 hours.
Maintained reduced NRF2 target gene and protein expression with repeat daily dosing for 7 days.
Animal Model: NCG mice (inoculated 1 × 107 HCC95 cells subcutaneously into the dorsal flank)[3]
Dosage: 2 mg/kg; 10 mg/kg; 25 mg/kg; 50 mg/kg
Administration: p.o.; QD or BID
Result: Produced significant tumor growth inhibition compared to vehicle control (P ≤ 0.0001) across all tested doses.
Achieved durable suppression of tumor volume over 40 days of treatment.
Animal Model: Immunodeficient mice[3]
Dosage: 50 mg/kg
Administration: p.o.; QD or BID
Result: Induced tumor growth inhibition (TGI) across wild-type and NRF2/KEAP1/CUL3 mutant PDX models, with the highest responses in NRF2 pathway-mutant tumors.
Produced significant tumor volume suppression compared to vehicle (P ≤ 0.0001) in LU1258 (CUL3S231L) sqNSCLC, LU6403 (CUL3R699T) sqNSCLC, LU6407 (NRF2R34P) sqNSCLC, LU6917 (KEAP1E218K) sqNSCLC, and HN0696 (NRF2R34P) HNSCC models.
Achieved durable partial regression for at least 90 days in the HN0696 model with continued treatment.
Animal Model: DBA/2 mice (inoculated 2 × 105 KLN-205 cells subcutaneously into the dorsal flank)[3]
Dosage: 50 mg/kg
Administration: p.o.; QD
Result: Reduced lung tumor burden (evident via histologic analysis) in the orthotopic model.
Increased median overall survival from 30 days (vehicle) to 41 days (****, P < 0.0001) in the orthotopic model.
Significantly suppressed tumor volume compared to vehicle control (****, P ≤ 0.0001) in the heterotopic model.
Molecular Weight

345.78

Formula

C16H16ClN5O2
CAS No.
Appearance

Solid

Color

White to off-white

SMILES

C=CC(N1[C@H](C2=CC(C3=NC=NC(N)=N3)=CC(Cl)=C2)COCC1)=O
Shipping

Room temperature in continental US; may vary elsewhere.
Storage

4°C, stored under nitrogen

*In solvent : -80°C, 6 months; -20°C, 1 month (stored under nitrogen)

Purity & Documentation
References
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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:

VVD 0653034876-85-9VVD065VVD-065Molecular GluesKeap1-Nrf2lung cancerNRF2esophageal squamous cell carcinomahead-and-neck cancerCUL3proteasomal degradationuterine cancersKYSE70KEAP1Cys151Inhibitorinhibitorinhibit

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