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.
For research use only. We do not sell to patients.
- CAS No.: 1052645-73-4
- Formula: C19H23N5O2S
- Molecular Weight:385.48
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Storage:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Biological Activity
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Chemical Information
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Biological Activity
Description
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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CAS No. 1052645-73-4
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Molecular Weight 385.48
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Formula 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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Shipping
Room temperature in continental US; may vary elsewhere.
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Storage
Please store the product under the recommended conditions in the Certificate of Analysis.
Purity & Documentation
Select Batch:
Purity:
99.98%
Assay:
99.98%
ee.:
99.98%
References
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CH5164840 Related Classifications
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