2. Cell Cycle/DNA Damage Apoptosis Protein Tyrosine Kinase/RTK Metabolic Enzyme/Protease Autophagy
  3. DNA/RNA Synthesis Apoptosis FAK Src MMP Autophagy
  4. NEO212

NEO212 is an orally active, blood-brain barrier permeable conjugate of Temozolomide (TMZ) (HY-17364) and Perillyl Alcohol (POH) (HY-N7000), with potent anticancer activity. NEO212 overcomes classical TMZ resistance and DNA alkylation by depleting MGMT. By inhibiting the FAK/Src signaling pathway, NEO212 reduces the production of MMP2 and MMP9, induces mesenchymal-epithelial transition, and inhibits the migration, invasion and tumor progression of glioma stem cells. NEO212 disrupts autophagy flux to enhance mitochondrial apoptosis; it induces differentiation of acute myeloid leukemia (AML) cells into macrophages and proliferation arrest.

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NEO212

NEO212 Chemical Structure

CAS No. : 1361198-79-9

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NEO212 Related Antibodies

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RNASE L DNA Polymerases RNA Polymerases Helicases DNA Ligase

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Lck Fyn Blk Fgr Hck Lyn Yes SRC-3

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MMP-1 MMP-2 MMP-3 MMP-8 MMP-9 MMP-13 MMP-14 MMP-17 ADAM10 ADAM17 MMP-7 MMP-12 MMP-10 MMP ADAM8 MMP-19

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Description

NEO212 is an orally active, blood-brain barrier permeable conjugate of Temozolomide (TMZ) (HY-17364) and Perillyl Alcohol (POH) (HY-N7000), with potent anticancer activity. NEO212 overcomes classical TMZ resistance and DNA alkylation by depleting MGMT. By inhibiting the FAK/Src signaling pathway, NEO212 reduces the production of MMP2 and MMP9, induces mesenchymal-epithelial transition, and inhibits the migration, invasion and tumor progression of glioma stem cells. NEO212 disrupts autophagy flux to enhance mitochondrial apoptosis; it induces differentiation of acute myeloid leukemia (AML) cells into macrophages and proliferation arrest[1][2][3][4].

In Vitro

NEO212 (5-50 μM; 24 h) reversibly inhibits the migration of mesenchymal USC02 glioma stem cells at non-cytotoxic doses. Its migration inhibitory activity remains stable after 24 h and is independent of its short-acting cytotoxic DNA alkylating effect[1].
NEO212 (15 μM; 16 h) significantly reduces the invasive capacity of mesenchymal USC02 glioma stem cells and freshly isolated patient-derived glioma cells[1].
NEO212 (3-15 μM) reduces the expression levels of invasion-related proteins MMP2 and MMP9 in mesenchymal USC02 and proneural USC04 glioma stem cells[1].
NEO212 (3-15 μM) selectively blocks the activation of the FAK/Src signaling pathway and its downstream kinases in mesenchymal USC02 and proneural USC04 glioma stem cells, and its mechanism of action differs from the non-specific protein synthesis inhibitory effect of TMZ[1].
NEO212 (3-15 μM) reverses the EMT phenotype of mesenchymal USC02 glioma stem cells by regulating key EMT-related genes, and promotes the transition of neuronal progenitor-like USC04 glioma stem cells toward epithelial-like features[1].
NEO212 (25-300 μM; 48 h) inhibits the viability of human ovarian cancer cell lines A2780, SK-O-V3 and OVCAR-3 in a dose-dependent manner, and exhibits stronger efficacy than TMZ, POH, or their combination[2].
NEO212 (100 μM; 48 h) potently inhibits colony formation of human ovarian cancer cell lines A2780, SK-O-V3 and OVCAR-3, and exhibits greater efficacy than TMZ, POH, or their combination[2].
NEO212 (100 μM; 48 h) induces G2/M phase cell cycle arrest in A2780, SK-O-V3 and OVCAR-3 human ovarian cancer cells[2].
NEO212 (100 μM; 48 h) induces robust DNA damage in human ovarian cancer cell lines A2780 and SK-O-V3, which is evidenced by increased phosphorylation levels of ATM, CHEK1, CHEK2 and H2AFX[2].
NEO212 (100 μM; 48 h) primarily induces apoptosis in A2780, SK-O-V3 and OVCAR-3 human ovarian cancer cells via a caspase-dependent mitochondrial pathway, with a minor caspase-independent component[2].
NEO212 (100 μM; 48 h) induces mitochondrial fission and morphological damage in A2780 and SK-O-V3 human ovarian cancer cells, which is characterized by decreased aspect ratio of mitochondria and deformation of internal matrix[2].
NEO212 (100 μM; 48 h) induces mitochondrial dysfunction in human ovarian cancer cell lines A2780 and SK-O-V3, which is characterized by a significant decrease in mitochondrial transmembrane potential[2].
NEO212 (100 μM; 48 h) induces autophagosome accumulation in human ovarian cancer cell lines A2780 and SK-O-V3, but does not promote excessive autophagic degradation[2].
NEO212 (100 μM; 48 h) blocks autophagic flux in A2780 and SK-O-V3 human ovarian cancer cells by impairing lysosomal function and reducing autophagosome-lysosome fusion[2].
NEO212 (100 μM; 48 h) inhibits the nuclear translocation of TFEB in human ovarian cancer cell lines A2780 and SK-O-V3 by upregulating the phosphorylation levels of AKT and ERK, which in turn impairs lysosomal function[2].
NEO212 (1-100 μM; 4-5 days) potently reduces the viability of canine CLBL1 cells, canine CLL1390 cells, human HL60 cells, human THP1 cells, human Raji cells and human U937 cells, with IC50 values ranging from 1.7 to 42 μM; moreover, combined treatment with O6BG enhances its cytotoxicity against MGMT-highly expressing CLL1390 cells[3].
NEO212 (1-70 μM; 3-7 days) induces apoptosis in canine CLBL1 cells, canine CLL1390 cells, human HL60 cells, human Raji cells and human U937 cells, and remains active in TMZ-resistant CLL1390 cells[3].
NEO212 (0-100 μM; 5 days) potently inhibits the activity of human AML cell lines U937, 6D10, HL60, KG1 and THP1 in vitro, with IC50 values ranging from ≤ 5 μM to 50 μM, and exerts better efficacy than TMZ in MGMT-positive AML cells[4].
NEO212 (50-100 μM; 16-32 h) downregulates MGMT protein levels in a time- and concentration-dependent manner in human THP1 and HL60 acute myeloid leukemia (AML) cells, whereas TMZ does not alter MGMT levels[4].
NEO212 (30 μM; 1-5 days) stimulates the expression of macrophage differentiation marker genes in human cytarabine-resistant 6D10 AML cells[4].
NEO212 (10-100 μM; 3-5 days) significantly upregulates CD11b mRNA levels in human U937, 6D10, THP1 and HL60 AML cells in vitro, and this effect cannot be mimicked by equimolar mixtures of TMZ and POH[4].
NEO212 (10-100 μM; 3-5 days) upregulates the cell surface CD11b protein levels in human U937, 6D10, HL60 and THP1 AML cells in vitro, and this effect cannot be replicated by TMZ, POH or their equimolar mixture[4].

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

NEO212 Related Antibodies

Cell Migration Assay [1]

Cell Line: mesenchymal patient-derived glioma stem cells (USC02)
Concentration: 5, 15, 25 and 50 μM
Incubation Time: 24 h
Result: Showed dose-dependent impaired migration compared to vehicle-treated cells.
Caused no significant difference in viable cell count compared to vehicle controls after 24 h treatment.
Regained migratory ability after 24 h treatment followed by 48 h drug-free recovery, showing significantly larger wound area than cells treated continuously for 72 h.

Cell Invasion Assay[1]

Cell Line: mesenchymal patient-derived glioma stem cells (USC02), freshly derived patient glioma cells
Concentration: 15 μM
Incubation Time: 16 h
Result: Significantly decreased the invasion rate of USC02 cells, while TMZ and/or perillyl alcohol showed no significant effects.
Decreased invasion capacity in all five tested samples of freshly derived patient glioma cells, despite varying baseline invasion rates.

Cell Viability Assay[2]

Cell Line: A2780, SK-O-V3, OVCAR-3 human ovarian cancer cell lines
Concentration: 25, 50, 100, 150, 200, 300 μM
Incubation Time: 48 h
Result: Inhibited cell viability in a dose-dependent manner across all three cell lines, with stronger inhibitory effects than its individual constituents (TMZ, POH) and their combination.

Cell Cycle Analysis[2]

Cell Line: A2780, SK-O-V3, OVCAR-3 human ovarian cancer cell lines
Concentration: 100 μM
Incubation Time: 48 h
Result: Increased the population of cells in the G2/M phase and decreased the population in the G1 phase across all three cell lines, indicating G2/M arrest.

Western Blot Analysis[2]

Cell Line: A2780, SK-O-V3 human ovarian cancer cell lines
Concentration: 100 μM
Incubation Time: 48 h
Result: Induced higher levels of phosphorylated ATM (Ser1981), phosphorylated CHEK1 (Ser345), phosphorylated CHEK2 (Thr68), and phosphorylated H2AFX (Ser139) compared to TMZ, POH, or their combination, indicating stronger DNA damage.

Apoptosis Analysis[2]

Cell Line: A2780, SK-O-V3, OVCAR-3 human ovarian cancer cell lines
Concentration: 100 μM; 100 μM (with concurrent 20 μM Z-VAD-FMK or 10 μM Ac-LEHD-FMK)
Incubation Time: 48 h; 48 h
Result: Induced significantly higher levels of apoptotic and dead cells compared to TMZ, POH, or their combination in all three cell lines.
Both Z-VAD-FMK and Ac-LEHD-FMK significantly reduced NEO212-induced apoptosis, but did not completely block it.

Cell Cytotoxicity Assay[4]

Cell Line: human acute myeloid leukemia (AML) cell lines U937, 6D10, HL60, KG1, THP1
Concentration: 0-10 μM (U937, 6D10); 0-100 μM (HL60, KG1, THP1)
Incubation Time: 5 days
Result: Potently inhibited viability of all tested AML cell lines, with IC50 values of ≤ 5 μM for U937, 6D10, HL60, and KG1 cells; THP1 cells had an IC50 around 50 μM.
Was far more potent than TMZ in MGMT-positive HL60, KG1, and THP1 cells, and equally potent as TMZ in MGMT-negative U937 and 6D10 cells.
Did not have its cytotoxic potency mimicked by an equimolar mix of TMZ and POH.

Western Blot Analysis[4]

Cell Line: human AML cell lines THP1, HL60
Concentration: 50, 75, 100 μM (24 h incubation); 80 μM (16, 24, 32 h incubation); 60, 80 μM (24 h incubation)
Incubation Time: 16 h, 24 h, 32 h
Result: Caused striking down-regulation of MGMT protein levels in THP1 and HL60 cells, with the effect detectable as early as 16 h after treatment with 50 μM NEO212, and more pronounced in THP1 cells than HL60 cells.
Showed no effect on MGMT protein levels when compared to TMZ treatment at concentrations up to 200 μM.

Real Time qPCR[4]

Cell Line: human AML cell lines U937, 6D10, THP1, HL60
Concentration: 10 μM (U937, 6D10); 50 μM (THP1); 75, 100 μM (HL60)
Incubation Time: 3, 5 days (U937, 6D10, THP1); 5 days (HL60)
Result: Caused significant induction of CD11b transcript in all tested AML cell lines, with increases observed across different concentrations and time points.
Did not have its CD11b expression induction mimicked by an equimolar mix of TMZ and POH, while the positive control TPA did.
In Vivo

NEO212 (5-25 mg/kg; s.c.; 5 days on, 2 days off cycles for 35 days) significantly prolongs survival, delays tumor progression, and reduces glioma stem cell invasion in an orthotopic mouse model of glioblastoma[1].
NEO212 (25 mg/kg; daily; 15 days) exerts potent in vivo anti-ovarian cancer activity, slowing tumor growth to a final fold volume of ~10 relative to day 1, inducing tumor necrosis and apoptosis, and showing no significant systemic toxicity in BALB/c nude mice[2].
NEO212 (25 mg/kg; p.o.; once daily for 5 consecutive days per cycle; two cycles total) strikingly prolongs survival in mice bearing human or canine leukaemia/lymphoma xenografts, with 100% survival at 200 days in two models and superior efficacy to TMZ[3].
NEO212 (25 mg/kg; p.o.; once daily for 5 consecutive days per cycle; 3 total cycles) treatment achieves a 100% survival rate for >300 days, resulting in apparent curative activity against AraC-resistant AML in mice[4].
NEO212 (25 mg/kg; p.o.; once daily for 5 consecutive days per cycle; 2 total cycles) treatment achieves a 100% survival rate for >300 days, resulting in apparent curative activity against TMZ-resistant AML in mice[4].
NEO212 (100-200 mg/kg; p.o.; once daily; 5 consecutive days) is well tolerated in rats at doses up to 200 mg/kg administered over 5 consecutive days, with no severe myelosuppression or mortality observed[4].

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

Animal Model: NOD/SCID (8-10 week old male; intracranial implantation of luciferase-labeled mesenchymal USC02 glioma stem cells)[1]
Dosage: 5 mg/kg; 25 mg/kg
Administration: s.c.; 5 days on, 2 days off cycles for 35 days
Result: Prolonged mouse survival significantly.
Delayed tumor progression highly significantly.
Reduced invasion of human tumor cells into normal brain parenchyma, showing a clear distinct border between tumor and normal brain.
Animal Model: BALB/c nude (female, 4-6 weeks of age, subcutaneous inoculation of 5×106 SK-O-V3 cells)[2]
Dosage: 25 mg/kg
Administration: daily; 15 days
Result: Reduced final fold tumor volume relative to day 1 to ~10, compared to ~40 in DMSO control.
Induced necrotic foci in tumors via H&E staining.
Increased cleaved caspase-3 staining, indicating enhanced apoptosis.
Showed no statistically significant difference in body weight compared to control.
Caused no morphological/histological changes in major organs (heart, liver, spleen, lung, kidney).
Animal Model: NOD-SCID or NSG-SGM3 (female, 6-8 weeks old, implanted with human or canine leukaemia/lymphoma cells)[3]
Dosage: 25 mg/kg
Administration: p.o.; once daily for 5 consecutive days per cycle; two cycles total
Result: Prolonged survival significantly in all five tumour models.
Achieved 100% survival at 200 days in human HL60 leukaemia and canine CLL1390 leukaemia models.
Showed significantly prolonged survival compared to vehicle controls in human U937 leukaemia model.
Extended survival significantly longer than vehicle and TMZ-treated mice in human Raji lymphoma model.
Extended survival significantly longer than vehicle and TMZ-treated mice in canine CLBL1 lymphoma model.
Extended survival significantly longer than vehicle and TMZ-treated mice in canine CLL1390 leukaemia model.
Animal Model: NOD-SCID (female, 6-8 weeks old, injected intraperitoneally with 5×104 MGMT-negative, AraC-resistant 6D10 AML cells)[4]
Dosage: 25 mg/kg
Administration: p.o.; once daily for 5 consecutive days per cycle; 3 total cycles
Result: Ensured 100% of treated mice survived > 300 days without signs of disease.
Rendered human AML cells undetectable in blood via sensitive Alu sequence PCR assay.
Animal Model: NOD-SCID (female, 6-8 weeks old, injected intraperitoneally with 5×104 MGMT-positive, TMZ-resistant HL60 AML cells)[4]
Dosage: 25 mg/kg
Administration: p.o.; once daily for 5 consecutive days per cycle; 2 total cycles
Result: Ensured 100% of treated mice survived > 300 days without signs of disease.
Rendered human AML cells undetectable in blood via sensitive Alu sequence PCR assay.
Molecular Weight

372.39

Formula

C17H20N6O4
CAS No.
SMILES

C(NC(OCC=1CC[C@H](C(C)=C)CC1)=O)(=O)C2=C3N(C=N2)C(=O)N(C)N=N3
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Keywords:

NEO2121361198-79-9NEO 212NEO-212DNA/RNA SynthesisApoptosisFAKSrcMMPAutophagyPTK2 protein tyrosine kinase 2PTK2Focal adhesion kinaseMatrix metalloproteinasesA2780FAK/Src signaling pathwayglioblastoma multiformeovarian cancerTFEBacute myeloid leukemialymphomaleukaemiaglioma stem cellsMGMTInhibitorinhibitorinhibit

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