2. PI3K/Akt/mTOR Apoptosis MAPK/ERK Pathway Metabolic Enzyme/Protease Membrane Transporter/Ion Channel Cell Cycle/DNA Damage Protein Tyrosine Kinase/RTK
  3. PI3K mTOR Akt Apoptosis Paraptosis p38 MAPK Mitochondrial Metabolism P-glycoprotein CDK MMP HIF/HIF Prolyl-Hydroxylase VEGFR
  4. 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[1][2][3].

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DHW-221

DHW-221 Chemical Structure

CAS No. : 2378831-21-9

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DHW-221 Related Antibodies

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Description

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[1][2][3].

IC50 & Target[1]

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)

In Vitro

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.

DHW-221 Related Antibodies

Cell Proliferation Assay[1]

Cell Line: HCT116 cells
Concentration: 0.3, 1 and 3 μM
Incubation Time: 2 weeks
Result: Inhibited the formation of HCT116 cell clones in a concentration-dependent manner.
Almost completely inhibited the production of cell clones at 3 μM.

Cell Migration Assay [1]

Cell Line: HCT116 cells
Concentration: 0.3, 1 and 3 μM
Incubation Time: 0, 24 and 48 h
Result: Its inhibition ability increased in a concentration-dependent manner.

Cell Invasion Assay[1]

Cell Line: HCT116 cells
Concentration: 0.3, 1 and 3 μM
Incubation Time: 48 h
Result: Significantly inhibited HCT116 cell metastasis and invasiveness in a dose-dependent manner.

Cell Viability Assay[2]

Cell Line: A549 and A549/Taxol cells
Concentration: 0.075, 0.15, 0.3, 0.5, 1.2 and 2.4 μM
Incubation Time: 24, 48 and 72 h
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.

Cell Proliferation Assay[2]

Cell Line: A549 and A549/Taxol cells
Concentration: 0.15, 0.60 and 2.40 μM
Incubation Time: 2 weeks
Result: Decreased the colony formation ability of A549/Taxol and A549 cells in a concentration-dependent manner.

Cell Cytotoxicity Assay[2]

Cell Line: A549 and A549/Taxol cells
Concentration: 0.15, 0.60 and 2.40 μM
Incubation Time: 48 h
Result: Increased LDH release rates in A549 and A549/Taxol cells in a concentration-dependent manner.

Western Blot Analysis[2]

Cell Line: A549 and A549/Taxol cells
Concentration: 0.15, 0.60 and 2.40 μM
Incubation Time: 3, 6, 12, 24 and 48 h
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.

Immunofluorescence[2]

Cell Line: A549/Taxol cells
Concentration: 0.15, 0.60 and 2.40 μM
Incubation Time: 24 and 48 h
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.

Apoptosis Analysis[2]

Cell Line: A549 and A549/Taxol cells
Concentration: 0.15, 0.60 and 2.40 μM
Incubation Time: 12 h (for vacuolation), and 48 h (for apoptosis/MMP)
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).

Cell Cycle Analysis[2]

Cell Line: A549/Taxol cells
Concentration: 0.15, 0.60 and 2.40 μM
Incubation Time: 48 h
Result: Significantly reduced the proportion of cells in S phase and increased the proportion of cells in G0/G1 phase.

Cell Migration Assay [2]

Cell Line: A549 and A549/Taxol cells
Concentration: 0.05, 0.10 and 0.15 μM
Incubation Time: 0, 24 and 48 h
Result: Significantly decreased the wound healing rate compared to the control group in both A549 and A549/Taxol cells.

Cell Invasion Assay[2]

Cell Line: A549 and A549/Taxol cells
Concentration: 0.05, 0.10 and 0.15 μM
Incubation Time: 24 h
Result: Significantly reduced the number of cells that migrated and invaded through the chamber in A549/Taxol cells.

Western Blot Analysis[2]

Cell Line: A549/Taxol cells
Concentration: 0.05, 0.10 and 0.15 μM
Incubation Time: 48 h
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.
Parmacokinetics[3]
Species Dose Route Indicator value
Mice 10 mg/kg i.v. T1/2 3.7 h
Mice 10 mg/kg p.o. T1/2 7.1 h
Mice 10 mg/kg i.v. Tmax 0.083 h
Mice 10 mg/kg p.o. Tmax 3.0 h
Mice 10 mg/kg i.v. Cmax 67395.0 ng/mL
Mice 10 mg/kg p.o. Cmax 11761.7 ng/mL
Mice 10 mg/kg i.v. AUCall 261501.9 ng·h/mL
Mice 10 mg/kg p.o. AUCall 176495.5 ng·h/mL
Mice 10 mg/kg i.v. MRTINF_obs 4.7 h
Mice 10 mg/kg p.o. MRTINF_obs 11.4 h
Mice 10 mg/kg p.o. F 67.5 %
In Vivo

DHW-221 (10, 20, and 40 mg/kg, i.g., q.d. for 2 weeks) inhibits tumor growth without body weight change and toxicity through FOXO3a translocation in A549/Taxol cell-bearing mice[2].
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.

Animal Model: Male nude mice (4-6 weeks old) intravenously injected with A549/Taxol cells[2]
Dosage: 25 and 50 mg/kg
Administration: i.g., q.d. for 2 weeks
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.
Animal Model: Nude mice bearing HCC827 xenografts (Subcutaneous and orthotopic injection)[3]
Dosage: 10, 20 and 40 mg/kg
Administration: p.o., q.d. for 21 days
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).
Molecular Weight

552.55

Formula

C27H22F2N4O5S
CAS No.
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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Room temperature in continental US; may vary elsewhere.
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Please store the product under the recommended conditions in the Certificate of Analysis.
Purity & Documentation
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DHW-221 Related Classifications

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  • 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:

DHW-2212378831-21-9DHW221DHW 221PI3KmTORAktApoptosisParaptosisp38 MAPKMitochondrial MetabolismP-glycoproteinCDKMMPHIF/HIF Prolyl-HydroxylaseVEGFRPhosphoinositide 3-kinaseMammalian target of RapamycinPKBProtein kinase BP-gpPgpMultidrug resistance protein 1MDR1ATP-binding cassette sub-family B member 1ABCB1Cluster of differentiation 243CD243Cyclin dependent kinaseMatrix metalloproteinasesHypoxia-inducible factorsHIFsHIF-PHVascular endothelial growth factor receptorPan-PI3KPI3KαPI3KβPI3KγPI3K/AktapoptosisA549HCT116MCF-7T47Dlungcolonbreast cancerNSCLCFOXO3aMDRMAPKERHCC827Inhibitorinhibitorinhibit

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