https://nova.newcastle.edu.au/vital/access/ /manager/Index en-au 5 https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:30110 50 values in the cell proliferation assay, CEP701 was the most potent inhibitor; sunitinib and PKC412 were ranked second and third, respectively. Sunitinib was the most selective inhibitor, followed by PKC421 and CEP701. The potency of sunitinib and to a lesser extent CEP701 in inhibition of FLT3 autophosphorylation was lower than the cell proliferation inhibition, indicating that inhibition of FLT3 downstream proteins may contribute to the cellular effects. It was shown in this study that the docking procedure was able to differentiate FLT3 inhibitors from ineffective compounds. Additionally, interaction with the phosphate binding region in the ATP-binding pocket increased potency at the cost of selectivity. These findings can be applied in designing highly effective and selective inhibitors for FLT3 and other related kinases.]]> Wed 15 Dec 2021 16:10:04 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:27809 Wed 02 Mar 2022 14:24:39 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:451 Thu 25 Jul 2013 09:09:49 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:1249 Sat 24 Mar 2018 08:28:35 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:14546 Sat 24 Mar 2018 08:18:49 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:17365 Sat 24 Mar 2018 08:01:31 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:21263 1B adrenoceptor replacing the charged aspartate, D191, as well as a potential interaction partner, K331, with uncharged alanines to observe effects on ligand binding and receptor activation. Significant 4–6 fold reductions in affinity for the endogenous agonists, epinephrine and norepinephrine were observed for receptors with the D191A mutation in the second extracellular loop. While changes in EC₅₀ were observed, operational analysis yielded no apparent change in receptor activation. Based on these findings, we suggest that D191, in the second extracellular loop of the α_1B adrenoceptor, acts as a ‘point of first contact’ for the receptor׳s endogenous agonists. Implication of the non-conserved extracellular regions of the receptor in agonist binding makes it a potential target for the design of highly selective drugs.]]> Sat 24 Mar 2018 07:54:43 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:38228 Haemophilus influenzae (NTHi) infection drives the development of steroid-resistant allergic airway disease (SRAAD), exacerbates clinical symptoms, worsens quality of life, and accounts for most of the related healthcare burden. The poor understanding of the pathogenesis of SRAAD deters the development of more effective therapeutic strategies. Here, we established a murine model of NTHi infection-induced exacerbation of allergic airway disease. We showed that NTHi infection drove Th 17-mediated pulmonary neutrophilic inflammation, aggravated airway hyper-responsiveness, and upset the balance of MUC5AC and MUC5B expression. Dexamethasone treatment effectively inhibited the features of allergic airway disease but failed to reduce NTHi-induced exacerbation, which was associated with the hyper-phosphorylation of p38 mitogen-activated protein kinase (MAPK). Interestingly, inhibition of p38 using a specific inhibitor (SB203580) only partly suppressed the airway hyper-responsiveness and mucus hyper-secretion but failed to abrogate the infection-induced neutrophilic inflammatory response in SRAAD. However, SB203580 and dexamethasone co-treatment substantially suppressed all the features of NTHi-induced SRAAD. Our findings highlight the importance of p38 MAPK in the pathogenesis of NTHi-induced steroid resistance, and this combined treatment approach may be a novel strategy against steroid-resistant asthma.]]> Mon 16 Aug 2021 16:15:47 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:56186 Mon 12 Aug 2024 10:11:22 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:46080 Fri 11 Nov 2022 10:10:17 AEDT ]]>