CH5164840
CH5164840 is an orally active HSP90α/β inhibitor with Kd values of 0.52 and 1.4 nM, respectively. CH5164840 degrades client proteins such as HER2/HER3/EGFR and inhibits the PI3K/AKT and RAF/MEK/ERK pathways, inducing HSP70 and apoptosis (apoptosis). CH5164840 causes spindle dysfunction and centromere-positive micronuclei, without kinase inhibition or mutagenicity. CH5164840 exhibits antitumor efficacy in vivo and acts synergistically with Trastuzumab (HY-P9907) and Lapatinib (HY-50898). CH5164840 shows no significant bacterial mutagenicity. CH5164840 can be used in research related to gastric cancer, breast cancer, ovarian cancer, prostate cancer, and colorectal cancer.
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- No. CAS: 1052645-73-4
- Fòrmula: C19H23N5O2S
- Peso molecular:385.48
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Actividad biológica
Descripciòn
CH5164840 is an orally active HSP90α/β inhibitor with Kd values of 0.52 and 1.4 nM, respectively. CH5164840 degrades client proteins such as HER2/HER3/EGFR and inhibits the PI3K/AKT and RAF/MEK/ERK pathways, inducing HSP70 and apoptosis (apoptosis). CH5164840 causes spindle dysfunction and centromere-positive micronuclei, without kinase inhibition or mutagenicity. CH5164840 exhibits antitumor efficacy in vivo and acts synergistically with Trastuzumab (HY-P9907) and Lapatinib (HY-50898). CH5164840 shows no significant bacterial mutagenicity. CH5164840 can be used in research related to gastric cancer, breast cancer, ovarian cancer, prostate cancer, and colorectal cancer[1][2][3][4][5].
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HSP90α 0.52 nM (Kd) |
HSP90β 1.4 nM (Kd) |
Cellular Effect
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Cell Line
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Type | Value | Description | References |
|---|---|---|---|---|
| NCI-N87 | IC50 |
0.066 μM
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Antiproliferative activity against human NCI-N87 gastric cancer cells assessed as viability reduction incubated 4 days by Cell Counting Kit-8 assay.
Antiproliferative activity against human NCI-N87 gastric cancer cells assessed as viability reduction incubated 4 days by Cell Counting Kit-8 assay.
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22050138 |
| BT-474 | IC50 |
0.11 μM
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Antiproliferative activity against human BT-474 breast cancer cells assessed as viability reduction incubated 4 days by Cell Counting Kit-8 assay.
Antiproliferative activity against human BT-474 breast cancer cells assessed as viability reduction incubated 4 days by Cell Counting Kit-8 assay.
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22050138 |
| SK-BR-3 | IC50 |
0.067 μM
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Antiproliferative activity against human SK-BR-3 breast cancer cells assessed as viability reduction incubated 4 days by Cell Counting Kit-8 assay.
Antiproliferative activity against human SK-BR-3 breast cancer cells assessed as viability reduction incubated 4 days by Cell Counting Kit-8 assay.
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22050138 |
| MDA-MB-231 | IC50 |
0.26 μM
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Antiproliferative activity against human MDA-MB231 cells assessed as viability reduction incubated 4 days by Cell Counting Kit-8 assay.
Antiproliferative activity against human MDA-MB231 cells assessed as viability reduction incubated 4 days by Cell Counting Kit-8 assay.
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22050138 |
| SK-OV-3 | IC50 |
0.26 μM
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Antiproliferative activity against human SK-OV-3 ovarian cancer cells assessed as viability reduction incubated 4 days by Cell Counting Kit-8 assay.
Antiproliferative activity against human SK-OV-3 ovarian cancer cells assessed as viability reduction incubated 4 days by Cell Counting Kit-8 assay.
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22050138 |
| DU-145 | IC50 |
0.15 μM
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Antiproliferative activity against human DU145 prostate cancer cells assessed as viability reduction incubated 4 days by Cell Counting Kit-8 assay.
Antiproliferative activity against human DU145 prostate cancer cells assessed as viability reduction incubated 4 days by Cell Counting Kit-8 assay.
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22050138 |
| NCI-H460 | IC50 |
0.16 μM
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Antiproliferative activity against human NCI-H460 lung cancer cells assessed as viability reduction incubated 4 days by Cell Counting Kit-8 assay.
Antiproliferative activity against human NCI-H460 lung cancer cells assessed as viability reduction incubated 4 days by Cell Counting Kit-8 assay.
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22050138 |
| HCT-116 | IC50 |
0.15 μM
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Antiproliferative activity against human HCT116 colorectal cancer cells assessed as viability reduction incubated 4 days by Cell Counting Kit-8 assay.
Antiproliferative activity against human HCT116 colorectal cancer cells assessed as viability reduction incubated 4 days by Cell Counting Kit-8 assay.
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22050138 |
| NHDF | IC50 |
1.2 μM
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Antiproliferative activity against normal human dermal fibroblast NHDF-Ad cells assessed as viability reduction incubated 4 days by Cell Counting Kit-8 assay.
Antiproliferative activity against normal human dermal fibroblast NHDF-Ad cells assessed as viability reduction incubated 4 days by Cell Counting Kit-8 assay.
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22050138 |
| NCI-H460 | IC50 |
0.25 μM
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Antiproliferative activity against human NCI-H460 cells in resistant-cell assay assessed as viability reduction incubated 4 days by Cell Counting Kit-8 assay.
Antiproliferative activity against human NCI-H460 cells in resistant-cell assay assessed as viability reduction incubated 4 days by Cell Counting Kit-8 assay.
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22050138 |
| MDA-MB-231 | IC50 |
0.29 μM
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Antiproliferative activity against NQO1 609T mutant human MDA-MB-231 cells assessed as viability reduction incubated 4 days by Cell Counting Kit-8 assay.
Antiproliferative activity against NQO1 609T mutant human MDA-MB-231 cells assessed as viability reduction incubated 4 days by Cell Counting Kit-8 assay.
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22050138 |
In Vitro
Anti-cancerApoptosisBacterial InfectionCell Cycle RegulationOthers
Anti-cancer
CH5164840 (4 days) inhibits the proliferation of HER2-overexpressing and other cancer cell lines with IC50 values of 66-260 nM, whereas normal NHDF-Ad fibroblasts are less sensitive (IC50 1.2 μM)[1].
CH5164840 selectively binds tumor HSP90 rather than normal fibroblast HSP90 in multi-chaperone complexes (including HSP70/HOP/HSP40)[1].
CH5164840 (1 μM; 24-48 h) inhibits Lapatinib (HY-50898)-induced HER3 signaling and promotes HER2/EGFR degradation in NCI-N87 cells[1].
CH5164840 selectively binds tumor HSP90 rather than normal fibroblast HSP90 in multi-chaperone complexes (including HSP70/HOP/HSP40)[1].
CH5164840 (1 μM; 24-48 h) inhibits Lapatinib (HY-50898)-induced HER3 signaling and promotes HER2/EGFR degradation in NCI-N87 cells[1].
Anti-cancer
Apoptosis
Apoptosis
Bacterial Infection
Cell Cycle Regulation
Others
CH5164840 is a high-affinity HSP90α/β binding agent with a Kd of 0.52 nM for HSP90α and 1.4 nM for HSP90β[1].
CH516484 is selective for HSP90, does not inhibit a panel of 22 kinases, and shows no significant ATP-competitive binding to 400 kinases[1].
CH5164840 binds the N-terminal Hsp90α ATP site in the X-ray co-crystal structure (PDB 3VHD, 1.3 Å), with key interactions with Lys58, Ile96, and Met98[2].
CH5164840 has low hepatic microsomal clearance, at 0.28 and 2.3 μL/min/mg protein in human and mouse liver microsomes, respectively[2].
CH516484 is selective for HSP90, does not inhibit a panel of 22 kinases, and shows no significant ATP-competitive binding to 400 kinases[1].
CH5164840 binds the N-terminal Hsp90α ATP site in the X-ray co-crystal structure (PDB 3VHD, 1.3 Å), with key interactions with Lys58, Ile96, and Met98[2].
CH5164840 has low hepatic microsomal clearance, at 0.28 and 2.3 μL/min/mg protein in human and mouse liver microsomes, respectively[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
Western Blot Analysis[1]
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Cell Line:NCI-N87 gastric cancer cells
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Concentration:1 μM
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Incubation Time:48 h (Western blotting); 24 h (HSP90 co-immunoprecipitation)
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Result:This compound in combination with Lapatinib degraded HER2 and EGFR and decreased phosphorylation and downstream signals in NCI-N87 cells.
Lapatinib-induced HER3 returned to basal levels after this compound addition.
HER3 was strongly co-precipitated with HSP90 in Lapatinib-treated cells, and this was returned to basal levels by this compound.
Immunofluorescence[4]
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Cell Line:TK6 cells
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Concentration:0.5 μg/mL
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Incubation Time:24 h
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Result:Asymmetric spindle formation and blurry centrosomal foci were observed in metaphase cells after this compound exposure.
The asymmetric spindle appeared as a loosely packed assembly of relaxed microtubules.
Apoptosis Analysis[4]
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Cell Line:TK6 cells
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Concentration:0.05, 0.1, 0.3, 0.5, and 0.7 μg/mL
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Incubation Time:24 h
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Result:In TK6 cells, both HSP70 upregulation and micronucleus formation are induced in a dose-dependent manner.
The micronuclei are predominantly centromere-positive (as determined by FISH) and are associated with asymmetric spindle microtubules and the misalignment of chromosomes at metaphase.
Co-staining for γH2AX and caspase-3 reveals that the observed signals are primarily apoptotic (γH2AX+/caspase-3+), with only a minor increase in non-apoptotic (γH2AX+/caspase-3-) cells (peaking at 8.7% at a concentration of 0.5 μg/mL).
Furthermore, the Ames test yields negative results.
Parmacokinetics
In Vivo
Anti-cancer
CH5164840 (50 mg/kg; p.o.; q.d.; for 11 consecutive days) produces potent antitumor activity in NCI-N87, BT-474, MDA-MB231, MAXF-401, SK-OV-3, DU145, and HCT116 xenograft models, with ED50 values of 4.2, 2.1, 7.1, 11.0, 8.0, 9.5, and 6.7 mg/kg, respectively[1].
CH5164840 (12.5-50 mg/kg; p.o.; once or twice weekly for 11 consecutive days) produces potent dose-dependent antitumor activity in the NCI-N87 gastric cancer xenograft model and enhances the efficacy of combination with Trastuzumab (HY-P9907) or Lapatinib (HY-50898)[5].
CH5164840 (12.5-25 mg/kg; p.o.; once daily for 11 consecutive days) produces potent antitumor activity in the BT-474 breast cancer xenograft model and enhances the efficacy of combination with Trastuzumab or Lapatinib[5].
CH5164840 (50 mg/kg; p.o.; single dose) achieves tumor-selective Hsp90 inhibition in the NCI-N87 gastric cancer xenograft model, with prolonged tumor retention time, and reduced p-Akt in tumor tissue but not in normal tissue[5].
CH5164840 (12.5-50 mg/kg; p.o.; once or twice weekly for 11 consecutive days) produces potent dose-dependent antitumor activity in the NCI-N87 gastric cancer xenograft model and enhances the efficacy of combination with Trastuzumab (HY-P9907) or Lapatinib (HY-50898)[5].
CH5164840 (12.5-25 mg/kg; p.o.; once daily for 11 consecutive days) produces potent antitumor activity in the BT-474 breast cancer xenograft model and enhances the efficacy of combination with Trastuzumab or Lapatinib[5].
CH5164840 (50 mg/kg; p.o.; single dose) achieves tumor-selective Hsp90 inhibition in the NCI-N87 gastric cancer xenograft model, with prolonged tumor retention time, and reduced p-Akt in tumor tissue but not in normal tissue[5].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:athymic nude (BALB/c nu/nu; CAnN.Cg-Foxn1
/CrlCrlj nu/nu)[1] -
Dosage:50 mg/kg
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Administration:p.o.; q.d.; 11 consecutive days
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Result:Maximum TGI was 160%; ED50 was 4.2 mg/kg.
In NCI-N87 xenograft tumor lysates, HER2, HER3, EGFR, cyclinD1, and phospho-AKT protein levels decreased.
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Animal Model:athymic nude (BALB/c nu/nu; CAnN.Cg-Foxn1
/CrlCrlj nu/nu)[1] -
Dosage:50 mg/kg
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Administration:p.o.; q.d.; 11 consecutive days
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Result:Maximum TGI was 152%; ED50 was 2.1 mg/kg.
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Animal Model:athymic nude (BALB/c nu/nu; CAnN.Cg-Foxn1
/CrlCrlj nu/nu)[1] -
Dosage:50 mg/kg
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Administration:p.o.; q.d.; 11 consecutive days
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Result:TGI was 80%; ED50 was 7.1 mg/kg.
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Animal Model:athymic nude (BALB/c nu/nu; CAnN.Cg-Foxn1
/CrlCrlj nu/nu)[1] -
Dosage:50 mg/kg
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Administration:p.o.; q.d.; 11 consecutive days
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Result:TGI was 97%; ED50 was 11.0 mg/kg.
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Animal Model:athymic nude (BALB/c nu/nu; CAnN.Cg-Foxn1
/CrlCrlj nu/nu)[1] -
Dosage:50 mg/kg
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Administration:p.o.; q.d.; 11 consecutive days
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Result:TGI was 91%; ED50 was 8.0 mg/kg.
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Animal Model:athymic nude (BALB/c nu/nu; CAnN.Cg-Foxn1
/CrlCrlj nu/nu)[1] -
Dosage:50 mg/kg
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Administration:p.o.; q.d.; 11 consecutive days
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Result:TGI was 87%; ED50 was 9.5 mg/kg.
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Animal Model:athymic nude (BALB/c nu/nu; CAnN.Cg-Foxn1
/CrlCrlj nu/nu)[1] -
Dosage:25 mg/kg
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Administration:p.o.; q.d.; 11 consecutive days
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Result:TGI was 83%; ED50 was 6.7 mg/kg.
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Animal Model:athymic nude (BALB/c nu/nu; CAnN.Cg-Foxn1
/CrlCrlj nu/nu)[5] -
Dosage:50 mg/kg (tumor biomarker analysis); 25 mg/kg with Trastuzumab 30 mg/kg; 12.5 mg/kg with Lapatinib 100 mg/kg; 50 mg/kg once or twice weekly with Trastuzumab
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Administration:p.o.; i.p.; daily for 11 consecutive days; once or twice weekly
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Result:The daily oral administration of this compound resulted in dose-dependent antitumor efficacy with maximum TGI 160% in NCI-N87 xenografts.
Decreased HER2, HER3, EGFR, and phospho-AKT protein levels in NCI-N87 tumor lysates and inhibited downstream signals.
In combination with Trastuzumab, this compound (25 mg/kg) increased TGI to 167% in NCI-N87, compared with 56% for Trastuzumab alone.
In combination with Lapatinib, this compound (12.5 mg/kg) increased TGI to 155% in NCI-N87, compared with 45% for Lapatinib alone.
In combination with Trastuzumab, this compound (50 mg/kg) given once weekly or twice weekly produced TGI of 97% and 123%, respectively, compared with 69% for Trastuzumab alone.
No significant body weight loss was observed.
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Animal Model:athymic nude (BALB/c nu/nu; CAnN.Cg-Foxn1
/CrlCrlj nu/nu)[5] -
Dosage:25 mg/kg with Trastuzumab 30 mg/kg; 12.5 mg/kg with Lapatinib 100 mg/kg
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Administration:p.o.; i.p.; daily for 11 consecutive days
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Result:The daily oral administration of this compound resulted in dose-dependent antitumor efficacy with maximum TGI 152% in BT-474 xenografts.
In combination with Trastuzumab, this compound (25 mg/kg) increased TGI to 240% in BT-474, compared with 136% for Trastuzumab alone.
In combination with Lapatinib, this compound (12.5 mg/kg) increased TGI to 214% in BT-474, compared with 88% for Lapatinib alone.
No significant body weight loss was observed.
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Animal Model:athymic nude (BALB/c nu/nu; CAnN.Cg-Foxn1
/CrlCrlj nu/nu)[5] -
Dosage:50 mg/kg
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Administration:p.o.; single administration
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Result:After a single oral 50 mg/kg dose of this compound, greater this compound retention was observed in tumor tissues (half-life = 6.3 h) than in normal tissues and plasma.
this compound caused a reduction in Akt phosphorylation levels in tumor tissues but not in normal tissues.
Hsp70 induction was confirmed in tumor and normal tissues.
Chemical Information
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No. CAS 1052645-73-4
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Peso molecular 385.48
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Fòrmula C19H23N5O2S
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SMILES
O=C(NCCCNC1=O)CCSC2=CC(C3=CC1=C(C)C=C3C)=NC(N)=N2
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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
Select Batch:
Pureza:
99.98%
Assay:
99.98%
ee.:
99.98%
Referencias
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CH5164840 Related Classifications
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