PQ 401IGF1R inhibitor,potent and cell-permeable CAS# 196868-63-0 |
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Quality Control & MSDS
Number of papers citing our products
Chemical structure
3D structure
Cas No. | 196868-63-0 | SDF | Download SDF |
PubChem ID | 9549305 | Appearance | Powder |
Formula | C18H16ClN3O2 | M.Wt | 341.79 |
Type of Compound | N/A | Storage | Desiccate at -20°C |
Synonyms | PQ401,PQ-401 | ||
Solubility | DMSO : 14.29 mg/mL (41.81 mM; Need ultrasonic) H2O : < 0.1 mg/mL (insoluble) | ||
Chemical Name | 1-(5-chloro-2-methoxyphenyl)-3-(2-methylquinolin-4-yl)urea | ||
SMILES | CC1=NC2=CC=CC=C2C(=C1)NC(=O)NC3=C(C=CC(=C3)Cl)OC | ||
Standard InChIKey | YBLWOZUPHDKFOT-UHFFFAOYSA-N | ||
Standard InChI | InChI=1S/C18H16ClN3O2/c1-11-9-15(13-5-3-4-6-14(13)20-11)21-18(23)22-16-10-12(19)7-8-17(16)24-2/h3-10H,1-2H3,(H2,20,21,22,23) | ||
General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. |
Description | Insulin-like growth factor receptor (IGF1R) inhibitor. Suppresses IGF-stimulated IGF-IR autophosphorylation with an IC50 value of 12 μM. Inhibits growth of MCF-7 breast cancer cells in vitro and in vivo. |
PQ 401 Dilution Calculator
PQ 401 Molarity Calculator
1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
1 mM | 2.9258 mL | 14.6289 mL | 29.2577 mL | 58.5155 mL | 73.1443 mL |
5 mM | 0.5852 mL | 2.9258 mL | 5.8515 mL | 11.7031 mL | 14.6289 mL |
10 mM | 0.2926 mL | 1.4629 mL | 2.9258 mL | 5.8515 mL | 7.3144 mL |
50 mM | 0.0585 mL | 0.2926 mL | 0.5852 mL | 1.1703 mL | 1.4629 mL |
100 mM | 0.0293 mL | 0.1463 mL | 0.2926 mL | 0.5852 mL | 0.7314 mL |
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. |
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PQ401 is a novel, potent inhibitor of IGF-IR with IC50 of 12μM [1].
In human MCF-7 cells, PQ401 inhibited autophosphorylation of the IGF-IR with IC50 of 12 μM and autophosphorylation of the isolated kinase domain of the IGF-IR with IC50 < 1μM. In addition, PQ401 inhibited the growth of cultured breast cancer cells in serum at 10μM. PQ401 can decrease IGF-I-mediated signaling through the Akt antiapoptotic pathway. Twenty-four hours treatment of 15 μM PQ401 induced caspase-mediated apoptosis [1]. In small trigeminal ganglion neurons, PQ401 blocked the IGF-1-induced A-type K(+) currents (IA) that were associated with a hyperpolarizing shift in the voltage dependence of inactivation [2].
In vivo, a treatment with PQ401 triple per week reduced the growth rate of MCNeuA cells implanted into mice [1].
References:
[1]. Gable KL, Maddux BA, Penaranda C, Zavodovskaya M, Campbell MJ, Lobo M, Robinson L, Schow S, Kerner JA, Goldfine ID, Youngren JF. Diarylureas are small-molecule inhibitors of insulin-like growth factor I receptor signaling and breast cancer cell growth. Mol Cancer Ther. 2006 Apr;5(4):1079-86.
[2]. Wang H, Qin J, Gong S, Feng B, Zhang Y, Tao J. Insulin-like growth factor-1 receptor-mediated inhibition of A-type K(+) current induces sensory neuronal hyperexcitability through the phosphatidylinositol 3-kinase and extracellular signal-regulated kinase 1/2 pathways, independently of Akt. Endocrinology. 2014 Jan;155(1):168-79.
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PQ401, an IGF-1R inhibitor, induces apoptosis and inhibits growth, proliferation and migration of glioma cells.[Pubmed:25971682]
J Chemother. 2016;28(1):44-9.
Growth factor signalling pathways transduce extra-cellular physiological cues to guide cells to maintain critical cellular functions, including cell proliferation, survival and metabolism. Dysregulation of certain growth factor signalling pathways has been shown as a major route to promote tumourigenesis. Glioma is a type of aggressive malignant tumour with no effective systematic therapy so far. Overexpression or hyperactivation of IGF-1R has been observed to be tightly associated with glioma progression and poor prognosis. Here, we examined the biological effects of a specific IGF-1R inhibitor, PQ401, on suppressing U87MG glioma cell growth and migration. Specifically, we observed that PQ401 not only induced cellular apoptosis in U87MG cells and subsequently reduced cell viability and proliferation but also attenuated cell mobility in vitro. More importantly, through a mouse xenograft model, we observed that administration of PQ401 on mice led to suppression of glioma tumour growth in vivo. In summary, our study suggests that PQ401 may serve as a promising leading drug for treating glioma patients with elevated IGF-1R signalling.
Insulin-like growth factor-1 receptor-mediated inhibition of A-type K(+) current induces sensory neuronal hyperexcitability through the phosphatidylinositol 3-kinase and extracellular signal-regulated kinase 1/2 pathways, independently of Akt.[Pubmed:24080365]
Endocrinology. 2014 Jan;155(1):168-79.
Although IGF-1 has been implicated in mediating hypersensitivity to pain, the underlying mechanisms remain unclear. We identified a novel functional of the IGF-1 receptor (IGF-1R) in regulating A-type K(+) currents (IA) as well as membrane excitability in small trigeminal ganglion neurons. Our results showed that IGF-1 reversibly decreased IA, whereas the sustained delayed rectifier K(+) current was unaffected. This IGF-1-induced IA decrease was associated with a hyperpolarizing shift in the voltage dependence of inactivation and was blocked by the IGF-1R antagonist PQ-401; an insulin receptor tyrosine kinase inhibitor had no such effect. An small interfering RNA targeting the IGF-1R, or pretreatment of neurons with specific phosphatidylinositol 3-kinase (PI3K) inhibitors abolished the IGF-1-induced IA decrease. Surprisingly, IGF-1-induced effects on IA were not regulated by Akt, a common downstream target of PI3K. The MAPK/ERK kinase inhibitor U0126, but not its inactive analog U0124, as well as the c-Raf-specific inhibitor GW5074, blocked the IGF-1-induced IA response. Analysis of phospho-ERK (p-ERK) showed that IGF-1 significantly activated ERK1/2 whereas p-JNK and p-p38 were unaffected. Moreover, the IGF-1-induced p-ERK1/2 increase was attenuated by PI3K and c-Raf inhibition, but not by Akt blockade. Functionally, we observed a significantly increased action potential firing rate induced by IGF-1; pretreatment with 4-aminopyridine abolished this effect. Taken together, our results indicate that IGF-1 attenuates IA through sequential activation of the PI3K- and c-Raf-dependent ERK1/2 signaling cascade. This occurred via the activation of IGF-1R and might contribute to neuronal hyperexcitability in small trigeminal ganglion neurons.
Insulin-like growth factor-I stimulates differentiation of ATII cells to ATI-like cells through activation of Wnt5a.[Pubmed:23709620]
Am J Physiol Lung Cell Mol Physiol. 2013 Aug 1;305(3):L222-8.
Alveolar type II (ATII) epithelial cells play a crucial role in the repair and remodeling of the lung following injury. ATII cells have the capability to proliferate and differentiate into alveolar type I (ATI) cells in vivo and into an ATI-like phenotype in vitro. While previous reports indicate that the differentiation of ATII cells into ATI cells is a complex biological process, the underlying mechanism responsible for differentiation is not fully understood. To investigate factors involved in this differentiation in culture, we used a PCR array and identified several genes that were either up- or downregulated in ATI-like cells (day 6 in culture) compared with day 2 ATII cells. Insulin-like growth factor-I (IGF-I) mRNA was increased nearly eightfold. We found that IGF-I was increased in the culture media of ATI-like cells and demonstrated a significant role in the differentiation process. Treatment of ATII cells with recombinant IGF-I accelerated the differentiation process, and this effect was abrogated by the IGF-I receptor blocker PQ401. We found that Wnt5a, a member of the Wnt-Frizzled pathway, was activated during IGF-I-mediated differentiation. Both protein kinase C and beta-catenin were transiently activated during transdifferentiation. Knocking down Wnt5a using small-interfering RNA abrogated the differentiation process as indicated by changes in the expression of an ATII cell marker (prosurfactant protein-C). Treatment of wounded cells with either IGF-I or Wnt5a stimulated wound closure. These results suggest that IGF-I promotes differentiation of ATII to ATI cells through the activation of a noncanonical Wnt pathway.
Diarylureas are small-molecule inhibitors of insulin-like growth factor I receptor signaling and breast cancer cell growth.[Pubmed:16648580]
Mol Cancer Ther. 2006 Apr;5(4):1079-86.
In breast and certain other cancers, receptor tyrosine kinases, including the insulin-like growth factor I receptor (IGF-IR), play an important role in promoting the oncogenic process. The IGF-IR is therefore an important target for developing new anti-breast cancer therapies. An initial screening of a chemical library against the IGF-IR in breast cancer cells identified a diaryl urea compound as a potent inhibitor of IGF-IR signaling. This class of compounds has not been studied as inhibitors of the IGF-IR. We studied the effectiveness of one diaryl urea compound, PQ401, at antagonizing IGF-IR signaling and inhibiting breast cancer cell growth in culture and in vivo. PQ401 inhibited autophosphorylation of the IGF-IR in cultured human MCF-7 cells with an IC50 of 12 micromol/L and autophosphorylation of the isolated kinase domain of the IGF-IR with an IC50 <1 micromol/L. In addition, PQ401 inhibited the growth of cultured breast cancer cells in serum at 10 micromol/L. PQ401 was even more effective at inhibiting IGF-I-stimulated growth of MCF-7 cells (IC50, 6 micromol/L). Treatment of MCF-7 cells with PQ401 was associated with a decrease in IGF-I-mediated signaling through the Akt antiapoptotic pathway. Twenty-four hours of treatment with 15 micromol/L PQ401 induced caspase-mediated apoptosis. In vivo, treatment with PQ401 (i.p. injection thrice a week) reduced the growth rate of MCNeuA cells implanted into mice. These studies indicate that diaryl urea compounds are potential new agents to test in the treatment of breast and other IGF-I-sensitive cancers.
The effects of type 1 IGF receptor inhibition in a mouse model of diabetic kidney disease.[Pubmed:21865067]
Growth Horm IGF Res. 2011 Oct;21(5):285-91.
OBJECTIVE: We have recently shown increased sensitivity to IGF-I induced signal transduction in kidneys of diabetic mice. Accordingly we investigated the effects of PQ401, a novel diarylurea compound that inhibits IGF1R autophosphorylation in type I diabetes. METHODS: Control (C) and Diabetic (D) mice were administered PQ401 (CP, DP) or vehicle (C, D) for 3weeks. RESULTS: CP animals showed a decrease in renal phosphorylated (p-)AKT and p-IGF1R. However, PQ401 had no effect on diabetic state (hyperglycemia, weight loss) or renal disease parameters (hypertrophy, hyperfiltration and albuminuria). Type IV collagen as well as TGF-beta mRNA increased in DP and D compared to C. In the CP group renal hypertrophy with fat accumulation in proximal tubuli and increased renal IGF-I, collagen IV and TGF-beta mRNA were seen. CONCLUSIONS: IGF1R inhibition by PQ401 exerted no significant effects on diabetic kidney disease parameters, arguing against a role for IGF-I in the pathogenesis of diabetic kidney disease. However, PQ401 affects normal kidneys, inducing renal hypertrophy as well as collagen and fat accumulation, with increased renal IGF-I mRNA, suggestive of a damage-regeneration process. Therefore, this diarylurea compound is not beneficial in early diabetic kidney disease. Its potential deleterious effects on kidney tissue need to be further investigated.
Autocrine loop for IGF-I receptor signaling in SLUG-mediated epithelial-mesenchymal transition.[Pubmed:19148466]
Int J Oncol. 2009 Feb;34(2):329-38.
Akt, a downstream effector kinase of insulin receptor and insulin-like growth factor-I receptor (IGF-IR), is critically involved in epithelial-mesenchymal transition (EMT). The aim of this study was to assess the impact of SLUG in the IGF/IGF-IR/Akt axis. The SLUG-overexpressing MDCK (SLUG-MDCK) cell clones were used as the EMT model. In contrast to the parental cells and mock-transfected MDCK cells, SLUG-MDCK cells were markedly sensitive to IGFs, showing a clear tyrosine-phosphorylation in IGF-IR under serum-starved conditions. The IGF-IR of hepatocytes was highly activated by culture supernatants from SLUG-MDCK cells. This activation was inhibited by IGF-binding protein (IGFBP)-3, and by the IGF-IR inhibitor PQ401, leading to inactivation of Akt. This finding suggested establishment of autocrine IGF-IR signaling in the SLUG-MDCK cells. It is known that cells overexpressing receptor tyrosine kinases have an increased activity in Src kinase, which constitutively phosphorylates IGF-IR. In the present study, we found an increased phosphorylation of Src in SLUG-MDCK cells, and not in mock-MDCK cells; however, this Src activation was not always coupled with the constitutive activation of IGF-IR, since the specific Src inhibitor PP2 failed to decrease the IGF-IR phosphorylation. PP2 just attenuated the phosphorylation in Akt, not through IGF-IR inactivation, leading to apoptosis in SLUG-MDCK cells. Of interest, the inactivation of Akt by IGFBP-3 was dramatically enhanced in combination with the use of PP2, resulting in a significant apoptosis in SLUG-MDCK cells. These findings suggested that dual targeting for IGF-IR and Src might be a potential therapeutic strategy in EMT-driven aggressive cancers.
Parallel synthesis of diarylureas and their evaluation as inhibitors of insulin-like growth factor receptor.[Pubmed:16961415]
J Comb Chem. 2006 Sep-Oct;8(5):784-90.
Diarylurea (DAU) compounds, particularly species composed of a heteroaryl ring system conjugated through a urea linkage to a substituted arene, were previously identified by the screening of a diverse chemical library to be active against the insulin growth factor receptor (IGF-1R). DAU compounds 4{a,b} were synthesized in parallel by the coupling of aryl amines 2{a} with aryl isocyanates 3{b}. Preparative RP-HPLC purification was found necessary to remove an impurity 5{b}, the symmetric urea resulting from the hydrolytic degradation of aryl isocyanates. Two libraries of DAU compounds were prepared to perform preliminary optimization of the two-ring systems for inhibitory activity against IGF-1R. In the first library, we explored a series of heteroaryl ring systems and found the 4-aminoquinaldine ring system to be optimal among those evaluated. The second library fixed the 4-aminoquinaldine ring system and we evaluated a series of substituted arenes conjugated to it. Overall, eight compounds based on the 4-aminoquinaldine heteroaryl system were found to have moderate activity against IGF-1R with IC(50) values better than 40 microM.