PD 90780
目录号 : GC34703An inhibitor of NGF-p75 NGFR interactions
Cas No.:77422-99-2
Sample solution is provided at 25 µL, 10mM.
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PD 90780 is an inhibitor of the interaction between NGF and the p75 NGF receptor (NGFR).1 It binds to NGF (KD = 25.83 μM) and inhibits NGF binding to the extracellular domain of p75 NGFR (IC50 = 220 nM), as well as to Q1-CHO cells expressing full-length human p75 NGFR (IC50 = 300 nM).1,2 PD 90780 inhibits NGF-dependent differentiation of PC12 cells (IC50 = 33.22 μM).2
1.Spiegel, K., Agrafiotis, D., Caprathe, B., et al.PD 90780, a non peptide inhibitor of nerve growth factor's binding to the P75 NGF receptorBiochem. Biophys. Res. Commun.217(2)488-494(1995) 2.Kennedy, A.E., Laamanen, C.A., Ross, M.S., et al.Nerve growth factor inhibitor with novel-binding domain demonstrates nanomolar efficacy in both cell-based and cell-free assay systemsPharmacol. Res. Perspect.5(5)e00339(2017)
Cas No. | 77422-99-2 | SDF | |
Canonical SMILES | CN1C2=CC(C(O)=O)=NN2C(C3=CC(NC(C4=CC=CC=C4)=O)=CC=C13)=O | ||
分子式 | C19H14N4O4 | 分子量 | 362.34 |
溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
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1 mM | 2.7598 mL | 13.7992 mL | 27.5984 mL |
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10 mM | 0.276 mL | 1.3799 mL | 2.7598 mL |
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PD 90780, a non peptide inhibitor of nerve growth factor's binding to the P75 NGF receptor
Nerve growth factor is a peptide that supports the survival and differentiation of discrete neuronal populations in the peripheral and central nervous systems. NGF binds to both trkA, a tyrosine kinase receptor, and to the p75 nerve growth factor receptor, a protein lacking a consensus signalling sequence. We have identified a substituted pyrazoloquinazolinone, PD 90780, which inhibits binding of nerve growth factor to the p75 receptor. This inhibition of binding occurs due to PD 90780 binding to nerve growth factor, not to the p75 receptor. This compound may be useful in identifying the region(s) of nerve growth factor involved in binding to the p75 receptor and in clarifying the role of p75 receptor in the actions of the neurotrophins.
Identification of novel pyrazoloquinazolinecarboxilate analogues to inhibit nerve growth factor in vitro
Nerve growth factor (NGF) is known to regulate the development and survival of select populations of neurons via its binding/activation of the TrkA and p75(NTR) receptors. However, in some physiological circumstances NGF dysregulation can result in debilitating pathologies, including diabetic neuropathies, interstitial cystitis and fibromyalgia. Thus, the identification of small molecules which inhibit NGF signalling have significant therapeutic potential. PD 90780, Ro 08-2750, and ALE 0540 are small molecules that have been reported to bind and inhibit NGF activity. Importantly, the docking site of these compounds is hypothesised to occur at the loop I/IV cleft of NGF-a region which is required for efficient and selective binding of this neurotrophin to its receptor(s). Molecular modelling predicts a number of previously reported NGF antagonists (PD 90780, ALE 0540, and Ro 08-2750) share conserved molecular features, and these drug-like small molecules have the ability to bind and modify the molecular topology of NGF. In order to understand the putative mechanism of binding, we synthesised a pyrazoloquinazolinecarboxilate analogue series and tested each compound in an NGF-dependent PC12 cell differentiation assay. In vitro data confirms that the pyrazoloquinazolinecarboxilate analogues functionally inhibit NGF's effects on PC12 cell differentiation. The results of this study provide evidence to refine the docking mode of pyrazoloquinazolinecarboxilate based compounds for the purposes of inhibiting NGF in vitro. In addition, we identified series analogue PQC 083 (IC50=7.0 ?M; CI=5.4-10.1 ?M) which displays markedly higher potency than previously described NGF antagonists.
IFT80 Improves Invasion Ability in Gastric Cancer Cell Line via ift80/p75NGFR/MMP9 Signaling
The assembly and maintenance of cilia depend on intraflagellar transport (IFT) proteins, which play an important role in development and homeostasis. IFT80 is a newly defined IFT protein and partial mutation of IFT80 in humans causes diseases such as Jeune asphyxiating thoracic dystrophy (JATD) and short rib polydactyly (SRP) type III, both characterized by abnormal skeletal development. However, the role and mechanism of IFT80 in the invasion of gastric cancer is unknown. We established SGC-7901 and MKN-45 gastric cancer cell lines that stably overexpressed IFT80, as verified by quantitative reverse transcription-PCR, Western blot, and immunofluorescence. Matrix metalloproteinase-9 (MMP9) plays an important role in tumor invasion, and its expression was assessed by quantitative reverse transcription-PCR, Western blotting, and immunofluorescence. The invasion ability of IFT80 on SGC-7901 and MKN-45 cells was examined by the Matrigel invasion assay. The relationship between p75NGFR, and the p75NGFR antagonists, PD90780 and IFT80, were detected by quantitative reverse transcription-PCR and Western blotting. We first detected an IFT80 expression pattern, and found that IFT80 was highly expressed in gastric cancer clinical samples. Overexpression of IFT80 in the gastric cancer cell lines, SGC-7901 and MKN-45, led to lengthening cilia. Additionally, overexpression of IFT80 significantly improved proliferation and invasion, but inhibited apoptosis, in gastric cancer cells. We further found that overexpression of IFT80 increased p75NGFR and MMP9 mRNA and protein expression. Treatment with the p75NGFR antagonist PD90780 inhibited the increased invasion ability resulting from overexpression of IFT80 in SGC-7901 and MKN-45 gastric cancer cells. Thus, these results suggest that IFT80 plays an important role in invasion of gastric cancer through regulating the ift80/p75NGFR/MMP9 signal pathways.
Role of p75NTR in female rat urinary bladder with cyclophosphamide-induced cystitis
Previous studies demonstrated changes in urinary bladder neurotrophin content and upregulation of neurotrophin receptors, TrkA and the p75 neurotrophin receptor (p75(NTR)), in micturition reflex pathways after cyclophosphamide (CYP)-induced cystitis. p75(NTR) can bind nerve growth factor (NGF) and modulate NGF-TrkA binding and signaling. We examined p75(NTR) expression and the role of p75(NTR) in the micturition reflex in control and CYP-treated rats. p75(NTR) Immunoreactivity was present throughout the urinary bladder. CYP-induced cystitis (4 h, 48 h, chronic) increased (P < or = 0.05) p75(NTR) expression in whole urinary bladder as shown by Western blotting. The role of p75(NTR) in bladder function in control and CYP-treated rats was determined using conscious cystometry and immunoneutralization or PD90780, a compound known to specifically block NGF binding to p75(NTR). An anti-p75(NTR) monoclonal antibody or PD90780 was infused intravesically and cystometric parameters were evaluated. Both methods of p75(NTR) blockade significantly (P < or = 0.05) decreased the intercontraction interval and void volume in control and CYP-treated rats. Intravesical infusion of PD90780 also significantly (P < or = 0.001) increased intravesical pressure and increased the number of nonvoiding contractions during the filling phase. Control intravesical infusions of isotype-matched IgG and vehicle were without effect. Intravesical instillation of PD90780 significantly (P < or = 0.01) reduced the volume threshold to elicit a micturition contraction in control rats (no inflammation) and CYP-treated in a closed urinary bladder system. These studies demonstrate 1) ubiquitous p75(NTR) expression in urinary bladder and increased expression with CYP-induced cystitis and 2) p75(NTR) blockade at the level of the urinary bladder produces bladder hyperreflexia in control and CYP-treated rats. The overall activity of the urinary bladder reflects the balance of NGF-p75(NTR) and NGF-TrkA signaling.