ORCID Profile
0000-0002-3188-596X
Current Organisations
Monash University
,
University of Queensland
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Sustainable design | Timber engineering | Automation and technology in building and construction | Building |
Publisher: Elsevier BV
Date: 10-2009
DOI: 10.1016/J.BMCL.2009.08.039
Abstract: The design and synthesis of a novel series of non-nucleoside HIV reverse transcriptase inhibitors (NNRTIs) based on a pyrazole template is described. These compounds are active against wild type reverse transcriptase (RT) and retain activity against clinically important mutants.
Publisher: American Chemical Society (ACS)
Date: 10-08-2017
DOI: 10.1021/ACS.JMEDCHEM.7B00598
Abstract: A series of acidic diaryl ether heterocyclic sulfonamides that are potent and subtype selective Na
Publisher: Wiley
Date: 15-10-2001
DOI: 10.1002/1521-3765(20011015)7:20<4465::AID-CHEM4465>3.0.CO;2-W
Abstract: Catalytic, enantioselective, tandem carbonyl ylide formation/cycloaddition of 2-diazo-3,6-diketoester 2 with the use of dirhodium tetrakiscarboxylate and tetrakisbinaphtholphosphate catalysts to give the cycloadducts 3 in good yields and up to 90% ee is described.
Publisher: American Chemical Society (ACS)
Date: 07-03-2008
DOI: 10.1021/OL800108U
Abstract: An efficient enantioselective total synthesis of (R)-rolipram and an efficient enantioselective formal synthesis of (3S,4R)-paroxetine has been achieved using the highly enantioselective Michael addition of malonate nucleophiles as key steps in both cases.
Publisher: Elsevier BV
Date: 2017
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C7MD00131B
Abstract: An aryl ether series of potent and selective Na v 1.3 inhibitors is described, starting from a series of diphenymethyl amides.
Publisher: Elsevier BV
Date: 09-1997
Publisher: Wiley
Date: 20-06-2011
Publisher: Elsevier BV
Date: 12-2023
Publisher: American Chemical Society (ACS)
Date: 04-11-2016
DOI: 10.1021/ACS.JMEDCHEM.6B00850
Abstract: The neurotrophin family of growth factors, comprised of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4), is implicated in the physiology of chronic pain. Given the clinical efficacy of anti-NGF monoclonal antibody (mAb) therapies, there is significant interest in the development of small molecule modulators of neurotrophin activity. Neurotrophins signal through the tropomyosin related kinase (Trk) family of tyrosine kinase receptors, hence Trk kinase inhibition represents a potentially "druggable" point of intervention. To deliver the safety profile required for chronic, nonlife threatening pain indications, highly kinase-selective Trk inhibitors with minimal brain availability are sought. Herein we describe how the use of SBDD, 2D QSAR models, and matched molecular pair data in compound design enabled the delivery of the highly potent, kinase-selective, and peripherally restricted clinical candidate PF-06273340.
Publisher: Proceedings of the National Academy of Sciences
Date: 22-08-2019
Abstract: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are an established treatment in estrogen receptor-positive breast cancer and are currently in clinical development in melanoma, a tumor that exhibits high rates of CDK4 activation. We analyzed melanoma cells with acquired resistance to the CDK4/6 inhibitor palbociclib and demonstrate that the activity of PRMT5, a protein arginine methyltransferase and indirect target of CDK4, is essential for CDK4/6 inhibitor sensitivity. By indirectly suppressing PRMT5 activity, palbociclib alters the pre-mRNA splicing of MDM4, a negative regulator of p53, leading to decreased MDM4 protein expression and subsequent p53 activation. In turn, p53 induces p21, leading to inhibition of CDK2, the main kinase substituting for CDK4/6 and a key driver of resistance to palbociclib. Loss of the ability of palbociclib to regulate the PRMT5–MDM4 axis leads to resistance. Importantly, combining palbociclib with the PRMT5 inhibitor GSK3326595 enhances the efficacy of palbociclib in treating naive and resistant models and also delays the emergence of resistance. Our studies have uncovered a mechanism of action of CDK4/6 inhibitors in regulating the MDM4 oncogene and the tumor suppressor, p53. Furthermore, we have established that palbociclib inhibition of the PRMT5–MDM4 axis is essential for robust melanoma cell sensitivity and provide preclinical evidence that coinhibition of CDK4/6 and PRMT5 is an effective and well-tolerated therapeutic strategy. Overall, our data provide a strong rationale for further investigation of novel combinations of CDK4/6 and PRMT5 inhibitors, not only in melanoma but other tumor types, including breast, pancreatic, and esophageal carcinoma.
Publisher: Royal Society of Chemistry (RSC)
Date: 1999
DOI: 10.1039/A906787F
Publisher: Elsevier BV
Date: 11-2018
Publisher: Elsevier BV
Date: 10-1997
Publisher: AIP Publishing
Date: 11-2019
DOI: 10.1063/1.5122849
Abstract: The WD40-repeat protein WDR5 scaffolds various epigenetic writers and is a critical component of the mammalian SET/MLL histone methyltransferase complex. Dysregulation of the MLL1 catalytic function is associated with mixed-lineage leukemia, and antagonism of the WDR5-MLL1 interaction by small molecules has been proposed as a therapeutic strategy for MLL-rearranged cancers. Small molecule binders of the “WIN” site of WDR5 that cause displacement from chromatin have been additionally implicated to be of broader use in cancer treatment. In this study, a fragment screen with Surface Plasmon Resonance (SPR) was used to identify a highly ligand-efficient imidazole-containing compound that is bound in the WIN site. The subsequent medicinal chemistry c aign—guided by a suite of high-resolution cocrystal structures with WDR5—progressed the initial hit to a low micromolar binder. One outcome from this study is a moiety that substitutes well for the side chain of arginine a tripeptide containing one such substitution was resolved in a high resolution structure (1.5 Å) with a binding mode analogous to the native tripeptide. SPR furthermore indicates a similar residence time (kd = ∼0.06 s−1) for these two analogs. This novel scaffold therefore represents a possible means to overcome the potential permeability issues of WDR5 ligands that possess highly basic groups like guanidine. The series reported here furthers the understanding of the WDR5 WIN site and functions as a starting point for the development of more potent WDR5 inhibitors that may serve as cancer therapeutics.
Publisher: Elsevier BV
Date: 10-2009
DOI: 10.1016/J.BMCL.2009.08.043
Abstract: Our efforts to reduce overall lipophilicity and increase ligand-lipophilicity efficiency (LLE) by modification of the 3- and 5-substituents of pyrazole 1, a novel non-nucleoside HIV reverse transcriptase inhibitor (NNRTI) prototype were unsuccessful. In contrast replacement of the substituted benzyl group with corresponding phenylthio or phenoxy groups resulted in marked improvements in potency, ligand efficiency (LE) and LLE.
Publisher: Proceedings of the National Academy of Sciences
Date: 20-04-2020
Publisher: Elsevier BV
Date: 10-2020
Publisher: Elsevier
Date: 2008
Publisher: Elsevier BV
Date: 05-2021
Publisher: Public Library of Science (PLoS)
Date: 06-04-2016
Publisher: Elsevier BV
Date: 02-2013
DOI: 10.1016/J.BMCL.2012.11.062
Abstract: Several non-benzimidazole containing inhibitors of respiratory syncytial virus are described. Core template modification, analysis of antiviral activity, physicochemistry and optimisation of properties led to the thiazole-imidazole 13, that showed a good potency and pharmacokinetic profile in the rat.
Publisher: Elsevier BV
Date: 12-2018
Publisher: Proceedings of the National Academy of Sciences
Date: 07-2013
Abstract: Voltage-gated sodium (Na v ) channels contribute to physiological and pathophysiological electrical signaling in nerve and muscle cells. Because Na v channel isoforms exhibit tissue-specific expression, subtype selective modulation of this channel family provides important drug development opportunities. However, most available Na v channel modulators are unable to distinguish between Na v channel subtypes, which limits their therapeutic utility because of cardiac or nervous system toxicity. This study describes a new class of subtype selective Na v channel inhibitors that interact with a region of the channel that controls voltage sensitivity. This interaction site may enable development of selective therapeutic interventions with reduced potential for toxicity.
Publisher: Royal Society of Chemistry (RSC)
Date: 2001
DOI: 10.1039/B000708K
Publisher: Informa UK Limited
Date: 04-10-2012
DOI: 10.3109/00498254.2011.617847
Abstract: Optimising drug properties can be an important strategy to limit penetration into the CNS and offers advantages in reducing the risk of undesirable neurological effects When considering the design of these drugs it is important to consider the relative influx and efflux rates at the relevant biological membranes The highest degree of restriction at the brain is probably achievable by utilising active transport to exclude compounds from the brain Affinity for the efflux transporters Pgp and BCRP has been achieved in two in-house chemistry programmes by increasing polar surface area, which resulted in highly orally bioavailable low CNS penetrant compounds in preclinical species.
Publisher: Elsevier BV
Date: 06-2018
Publisher: Elsevier BV
Date: 10-2023
Publisher: Elsevier BV
Date: 10-2009
DOI: 10.1016/J.BMCL.2009.08.080
Abstract: We prepared three discreet cohorts of potent non-nucleoside HIV reverse transcriptase inhibitors (NNRTIs) based on the recently reported 3-cyanophenoxypyrazole lead 3. Several of these compounds displayed very promising anti-HIV activity in vitro, safety, pharmacokinetic and pharmaceutical profiles. We describe our analysis and conclusions leading to the selection of alcohol 5 (UK-453,061, lersivirine) for clinical development.
Publisher: Georg Thieme Verlag KG
Date: 2002
DOI: 10.1055/S-2002-32577
Publisher: Research Square Platform LLC
Date: 02-09-2021
DOI: 10.21203/RS.3.RS-817595/V1
Abstract: Smouldering combustion has shown to be an effective application for soil remediation and as a waste treatment method for solids with high moisture content. The experimental set-up of smouldering combustion reactors is similar to autothermal fixed-bed gasification, updraft reactor configuration. In this study, smouldering experiments were conducted using lignocellulosic agricultural waste. The moisture content of lignocellulosic biomass was varied between 10 % to 50 %. Air flux was varied between 1.8 and 7.4 cm/s. Experiments were also conducted with varying oxygen concentration in the airflow (3.6 – 21 %), addition of sand (4 and 8 g/g) and other lignocellulosic material (wood pellets, and residual berry plant). Fuel gas with maximum H 2 , CO, CH 4 , CO 2 concentrations of 7.7, 32.6, 2.3, and 57.4 % (N 2 free) respectively were obtained with 10 % moisture content and 7.4 cm/s air flux. The smouldering yielded 1.24 Nm 3 /kg feed_dry of gas with calorific value of 1.82 MJ/Nm 3 (HHV).
Publisher: American Chemical Society (ACS)
Date: 03-12-2011
DOI: 10.1021/JM100978N
Abstract: Preventing entry of HIV into human host cells has emerged as an attractive approach to controlling viral replication. Maraviroc 1 is an approved antagonist of the human CCR5 receptor which prevents the entry of HIV. Herein, we report the design and discovery of a series of imidazopiperidine CCR5 antagonists which retain the attractive antiviral profile and window over hERG activity of maraviroc 1, combined with improved absorption profiles in rat and dog. Furthermore, this series of compounds has been shown to retain activity against a laboratory generated maraviroc-resistant HIV-1 strain, which indicates an alternative resistance profile to that of maraviroc 1. Compound 41f (PF-232798) was selected as a clinical candidate from the imidazopiperidine series and is currently in phase II clinical trials.
Publisher: American Chemical Society (ACS)
Date: 05-2007
DOI: 10.1021/OL070532L
Abstract: 5-Aryl-1,3-dioxolan-4-one heterocycles derived from mandelic acid derivatives and hexafluoroacetone have been identified as new and effective pro-nucleophiles in highly diastereo- and enantioselective Michael addition reactions to nitro olefins catalyzed by bifunctional epi-9-amino-9-deoxy cinchona alkaloid derivatives. Diastereoselectivities up to 98% and enantioselectivities up to 89% for a range of nitro olefins and 5-aryl-1,3-dioxolan-4-ones under mild reaction conditions are reported.
Start Date: 10-2023
End Date: 10-2028
Amount: $2,959,803.00
Funder: Australian Research Council
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