DHW-221
DHW-221 is a potent orally active dual PI3K/mTOR inhibitor, exhibiting low nanomolar potency against all four Class I PI3K isoforms and mTOR (PI3Kα, IC50 = 0.50 nM; PI3Kβ, IC50 = 1.9 nM; PI3Kγ, IC50 = 1.8 nM; PI3Kδ, IC50 = 0.74 nM; mTOR, IC50 = 3.9 nM). DHW-221 exerts antitumor effects by blocking the PI3K/Akt/mTOR pathway and inducing mitochondrial apoptosis and paraptosis (via Endoplasmic Reticulum (ER) stress and MAPK signaling) and arrests cell cycle, thereby inhibiting cell migration, invasion and angiogenesis. DHW-221 inhibits tumor growth in both the A549/Taxol (HY-B0015) and the HCC827 xenograft mouse models. DHW-221 can be used for non-small cell lung cancer (NSCLC), colon and breast cancer research.
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- No. CAS: 2378831-21-9
- Fòrmula: C27H22F2N4O5S
- Peso molecular:552.55
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Almacenamiento:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Actividad biológica
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Chemical Information
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Actividad biológica
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PI3Kα 0.50 nM (IC50) |
PI3Kβ 1.9 nM (IC50) |
PI3Kδ 0.74 nM (IC50) |
PI3Kγ 1.8 nM (IC50) |
mTOR 3.9 nM (IC50) |
DHW-221 (compound 8i) (72 h) shows antiproliferation activity against typically human cancer cells with IC50 values of 0.36 μM (T47D), 0.14 μM (HCT116), and 0.31 μM (MCF-7)[1].
DHW-221 (0.3-3 μM) decreases the phospho-Akt (S473) in a dose-dependent manner in HCT116 cells with no significant change in the expression of total protein Akt[1].
DHW-221 (0-5 μM, 2 weeks) inhibits the proliferation of HCT116 cells in a dose-dependent manner[1].
DHW-221 (0.3-3 μM, 0-48 h) inhibits HCT116 cell metastasis and invasiveness in a dose-dependent manner[1].
DHW-221 (0.3-3 μM) induces apoptosis in HCT116 cells in a concentration-dependent manner, with marked nuclear fragmentation and condensation of chromatin[1].
DHW-221 fits into the binding site of PI3K kinase similarly to Omipalisib (HY-10297), forming hydrogen bonds with Val882, Lys833, and Thr887, as well as Pi-Pi interactions with multiple amino acid residues[1].
DHW-221 (72 h) exhibits significant cytotoxicity in a concentration- and time-dependent manner in A549/Taxol (IC50 = 0.5274 μM) and A549 cells (IC50 = 0.4242 μM)[2].
DHW-221 (0-2.4 μM, 48-72 h) exerts significant inhibitory activity in MDR cancer cells (A549 and A549/Taxol cells), resulting in severe cellular damage at 48 h compared to control group in both cells[2].
DHW-221 (0.15-2.4 μM, 48 h) increases intracellular Rho-123 accumulation in a concentration-dependent manner in A549/Taxol cells and significantly downregulates P-gp expression, indicating that it inhibits P-gp function and protein expression[2].
DHW-221 (50 nM, 48 h) significantly enhances the cytotoxic effect of Taxol, an effect similar to the P-gp inhibitor Verapamil (HY-14275), suggesting that it functions as a P-gp inhibitor and a MDR reversal agent[2].
DHW-221 (0.15-2.4 μM, 12-48 h) triggers apoptosis and paraptosis in A549/Taxol cells through the mitochondrial pathway, ER stress and the MAPK signaling pathway[2].
DHW-221 (0.15-2.4 μM, 48 h) arrests the cell cycle at the G0/G1 phase in A549/Taxol and A549 cells by downregulating cyclin D1, CDK4, and CDK6, and upregulating p21[2].
DHW-221 (0.05-0.15 μM, 48 h) suppresses the migration and invasion capabilities of A549/Taxol cells through reversing epithelial-mesenchymal transition (EMT) phenotypic changes[2].
DHW-221 (0.15-2.4 μM, 48 h) significantly blocks the PI3K/Akt signaling pathway in both A549 and A549/Taxol cells, as demonstrated by decreased levels of PI3Kp110α and phosphorylated Akt (p-Akt)[2].
DHW-221 (25-400 nM, 1-3 h) inhibits endothelial tube formation in Human Umbilical Vein Endothelial Cells (HUVECs) by suppressing the PI3K/HIF-1α/VEGF signaling axis[3].
DHW-221 (1.56-6.25 µM) inhibits microvessel sprouting in rat aortic ring assays ex vivo[3].
DHW-221 (1.25-5 µM) inhibits neovascularization in chick chorioallantoic membranes without affecting embryo viability[3].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:HCT116 cells
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Concentration:0.3, 1 and 3 μM
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Incubation Time:2 weeks
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Result:Inhibited the formation of HCT116 cell clones in a concentration-dependent manner.
Almost completely inhibited the production of cell clones at 3 μM.
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Cell Line:HCT116 cells
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Concentration:0.3, 1 and 3 μM
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Incubation Time:0, 24 and 48 h
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Result:Its inhibition ability increased in a concentration-dependent manner.
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Cell Line:HCT116 cells
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Concentration:0.3, 1 and 3 μM
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Incubation Time:48 h
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Result:Significantly inhibited HCT116 cell metastasis and invasiveness in a dose-dependent manner.
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Cell Line:A549 and A549/Taxol cells
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Concentration:0.075, 0.15, 0.3, 0.5, 1.2 and 2.4 μM
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Incubation Time:24, 48 and 72 h
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Result:Exhibited significant cytotoxicity in a concentration- and time-dependent manner in A549/Taxol and A549 cells with an resistance index (RI) of 1.2.
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Cell Line:A549 and A549/Taxol cells
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Concentration:0.15, 0.60 and 2.40 μM
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Incubation Time:2 weeks
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Result:Decreased the colony formation ability of A549/Taxol and A549 cells in a concentration-dependent manner.
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Cell Line:A549 and A549/Taxol cells
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Concentration:0.15, 0.60 and 2.40 μM
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Incubation Time:48 h
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Result:Increased LDH release rates in A549 and A549/Taxol cells in a concentration-dependent manner.
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Cell Line:A549 and A549/Taxol cells
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Concentration:0.15, 0.60 and 2.40 μM
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Incubation Time:3, 6, 12, 24 and 48 h
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Result:Upregulated the expression levels of apoptosis-related proteins (cytochrome C, cleaved caspase 3, and cleaved PARP) in A549/Taxol cells in a concentration-dependent manner.
Downregulated the expression levels of the anti-apoptotic protein, Bcl-2, in A549/Taxol cells in a concentration-dependent manner.
Significantly inhibited the expression of Alix in A549/Taxol cells.
Significantly upregulated the expression levels of ATF4, CHOP (key regulator in ER stress), p-JNK, p-ERK, and p-p38 in A549/Taxol cells.
Decreased the expression levels of cyclin D1, CDK4, and CDK6 and increased p21 levels in A549/Taxol cells in a concentration-dependent manner.
Significantly decreased the expression levels of PI3Kp110a and p-Akt in a concentration-dependent manner, with no obvious change in the total Akt level in both cells.
Blocked the PI3K/Akt signaling pathway in both A549/Taxol and A549 cells.
Significantly downregulated p-FOXO3a (Ser253) expression and upregulated FOXO3a expression, accompanied by an increase in Bim expression in A549/Taxol cells.
Showed no significant changes in FOXO3a and Bim expression levels were observed in A549 cells.
Promoted FOXO3a accumulation in A549/Taxol cells when combined with MG132 (HY-13259).
Interfered with FOXO3a degradation in a proteasome-independent manner.
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Cell Line:A549/Taxol cells
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Concentration:0.15, 0.60 and 2.40 μM
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Incubation Time:24 and 48 h
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Result:Increased nuclear FOXO3a protein and decreased cytoplasmic phosphorylated FOXO3a at the Ser253 site.
Reversed the EMT phenotype, evidenced by enhanced fluorescence intensity of the epithelial marker occludin and weakened fluorescence of the mesenchymal marker vimentin.
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Cell Line:A549 and A549/Taxol cells
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Concentration:0.15, 0.60 and 2.40 μM
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Incubation Time:12 h (for vacuolation), and 48 h (for apoptosis/MMP)
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Result:Significantly increased the rates of early and late apoptosis in both A549/Taxol and A549 cells after 48 h.
Its pro-apoptotic ability in A549/Taxol cell was stronger than that of A549 cells at 2.4 μM.
Triggered apoptosis in A549/Taxol and A549 cells in a concentration-dependent manner.
Decreased the intracellular MMP in A549/Taxol cells after 48 h.
Induced the formation of massive vacuoles in A549/Taxol cells at 2.4 μM after 12 h.
Attenuated cytoplasmic vacuolation when combined with Cycloheximide (HY-12320, 20 μM).
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Cell Line:A549/Taxol cells
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Concentration:0.15, 0.60 and 2.40 μM
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Incubation Time:48 h
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Result:Significantly reduced the proportion of cells in S phase and increased the proportion of cells in G0/G1 phase.
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Cell Line:A549 and A549/Taxol cells
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Concentration:0.05, 0.10 and 0.15 μM
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Incubation Time:0, 24 and 48 h
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Result:Significantly decreased the wound healing rate compared to the control group in both A549 and A549/Taxol cells.
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Cell Line:A549 and A549/Taxol cells
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Concentration:0.05, 0.10 and 0.15 μM
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Incubation Time:24 h
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Result:Significantly reduced the number of cells that migrated and invaded through the chamber in A549/Taxol cells.
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Cell Line:A549/Taxol cells
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Concentration:0.05, 0.10 and 0.15 μM
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Incubation Time:48 h
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Result:Increased the expression levels of E-cadherin and occludin but significantly decreased the expression levels of mesenchymal markers, including vimentin and slug.
Decreased the expression of transcription factor snail.
Significantly downregulated the expression levels of MMP2 and MMP9 in A549/Taxol cells.
DHW-221 (10, 20, and 40 mg/kg, p.o., q.d. for 21 days) inhibits tumor growth in HCC827 xenograft mice model[3].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Male nude mice (4-6 weeks old) intravenously injected with A549/Taxol cells[2]
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Dosage:25 and 50 mg/kg
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Administration:i.g., q.d. for 2 weeks
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Result:Significantly decreased the number of lung nodules.
Downregulated p-FOXO3a expression and upregulated FOXO3a expression.
Showed no change in Ki67 expression.
Showed no significant differences in the body weight and viscera index compared to the control group.
Caused no behavioral abnormalities or loss of appetite.
Exhibited no evident histological abnormalities in the heart, liver, kidney, or spleen.
Resulted in no abnormal toxicity signs in serum biochemical parameters (CK, ALT, AST, CRE), indicating no cardiac, hepatic, or renal toxicity.
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Animal Model:Nude mice bearing HCC827 xenografts (Subcutaneous and orthotopic injection)[3]
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Dosage:10, 20 and 40 mg/kg
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Administration:p.o., q.d. for 21 days
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Result:Significantly inhibited tumor growth in both subcutaneous and orthotopic models.
Showed no significant effect on body weight.
Exhibited only mild liver toxicity at the high dose (40 mg/kg).
Chemical Information
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No. CAS 2378831-21-9
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Peso molecular 552.55
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Fòrmula C27H22F2N4O5S
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SMILES
O=S(C1=CC=C(F)C=C1F)(NC2=CC(C3=CC=C4C(N(C5=CC=C(OCCO)C=C5)C=N4)=C3)=CN=C2OC)=O
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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
[1]. Ding HW, et al. Design, synthesis, and biological evaluation of some novel 4-aminoquinazolines as Pan-PI3K inhibitors. Bioorg Med Chem. 2019 Jul 1;27(13):2729-2740. [Content Brief]
[2]. Liu M, et al. DHW-221, a Dual PI3K/mTOR Inhibitor, Overcomes Multidrug Resistance by Targeting P-Glycoprotein (P-gp/ABCB1) and Akt-Mediated FOXO3a Nuclear Translocation in Non-small Cell Lung Cancer. Front Oncol. 2022 May 13;12:873649. [Content Brief]
[3]. Qin X, et al. Dual blocking of PI3K and mTOR signaling by DHW-221, a novel benzimidazole derivative, exerts antitumor activity in human non-small cell lung cancer. Clin Transl Med. 2021 Sep;11(9):e514. [Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
DHW-221 Related Classifications
HY-130133 Related Classifications
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