A5067923134- Cyclopropane Reaction Mechanisms
- HIV/AIDS drug development and treatment
- Cancer-related gene regulation
- Synthesis and Catalytic Reactions
- HIV Research and Treatment
- Asymmetric Synthesis and Catalysis
- Ion channel regulation and function
- Synthetic Organic Chemistry Methods
- Catalytic C–H Functionalization Methods
- Genomics and Chromatin Dynamics
- Cardiac electrophysiology and arrhythmias
- Epigenetics and DNA Methylation
- Protein Degradation and Inhibitors
- Oxidative Organic Chemistry Reactions
- Radical Photochemical Reactions
- Ubiquitin and proteasome pathways
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Click Chemistry and Applications
- Cancer Genomics and Diagnostics
- Catalysis for Biomass Conversion
- Mechanisms of cancer metastasis
- Pneumocystis jirovecii pneumonia detection and treatment
- Lymphatic System and Diseases
- Synthesis and Reactivity of Heterocycles
Monash University
2018-2024
Walter and Eliza Hall Institute of Medical Research
2012-2019
Paediatric Integrated Cancer Service
2019
The University of Melbourne
2019
Commonwealth Scientific and Industrial Research Organisation
2019
Pfizer (United Kingdom)
2007-2017
Pfizer (United States)
1991-2017
University of Manchester
2007-2008
University of Oxford
1997-2003
Dyson (United Kingdom)
1997
Significance Voltage-gated sodium (Na v ) channels contribute to physiological and pathophysiological electrical signaling in nerve muscle cells. Because Na channel isoforms exhibit tissue-specific expression, subtype selective modulation of this family provides important drug development opportunities. However, most available modulators are unable distinguish between subtypes, which limits their therapeutic utility because cardiac or nervous system toxicity. This study describes a new class...
Human genetic studies show that the voltage gated sodium channel 1.7 (Nav1.7) is a key molecular determinant of pain sensation. However, defining Nav1.7 contribution to nociceptive signalling has been hampered by lack selective inhibitors. Here we report two potent and arylsulfonamide inhibitors; PF-05198007 PF-05089771, which have used directly interrogate Nav1.7’s role in nociceptor physiology. We predominant functional TTX-sensitive Nav mouse human nociceptors contributes initiation...
An efficient enantioselective total synthesis of (R)-rolipram and an formal (3S,4R)-paroxetine has been achieved using the highly Michael addition malonate nucleophiles as key steps in both cases.
Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are an established treatment in estrogen receptor-positive breast cancer and currently clinical development melanoma, a tumor that exhibits high rates of CDK4 activation. We analyzed melanoma cells with acquired resistance to the CDK4/6 inhibitor palbociclib demonstrate activity PRMT5, protein arginine methyltransferase indirect target CDK4, is essential for sensitivity. By indirectly suppressing PRMT5 activity, alters pre-mRNA splicing MDM4,...
KAT6A, and its paralog KAT6B, are histone lysine acetyltransferases (HAT) that acetylate H3K23 exert an oncogenic role in several tumor types including breast cancer where KAT6A is frequently amplified/overexpressed. However, pharmacologic targeting of to achieve therapeutic benefit has been a challenge. Here we describe identification highly potent, selective, orally bioavailable KAT6A/KAT6B inhibitor CTx-648 (PF-9363), derived from benzisoxazole series, which demonstrates anti-tumor...
The neurotrophin family of growth factors, comprised nerve factor (NGF), brain derived neurotrophic (BDNF), 3 (NT3), and 4 (NT4), is implicated in the physiology chronic pain. Given clinical efficacy anti-NGF monoclonal antibody (mAb) therapies, there significant interest development small molecule modulators activity. Neurotrophins signal through tropomyosin related kinase (Trk) tyrosine receptors, hence Trk inhibition represents a potentially "druggable" point intervention. To deliver...
A series of acidic diaryl ether heterocyclic sulfonamides that are potent and subtype selective NaV1.7 inhibitors is described. Optimization early lead matter focused on removal structural alerts, improving metabolic stability reducing cytochrome P450 inhibition driven drug-drug interaction concerns to deliver the desired balance preclinical in vitro properties. Concerns over nonmetabolic routes clearance, variable clearance species, subsequent low confidence human pharmacokinetic...
Catalytic, enantioselective, tandem carbonyl ylide formation/cycloaddition of 2-diazo-3,6-diketoester 2 with the use dirhodium tetrakiscarboxylate and tetrakisbinaphtholphosphate catalysts to give cycloadducts 3 in good yields up 90% ee is described.
5-Aryl-1,3-dioxolan-4-one heterocycles derived from mandelic acid derivatives and hexafluoroacetone have been identified as new effective pro-nucleophiles in highly diastereo- enantioselective Michael addition reactions to nitro olefins catalyzed by bifunctional epi-9-amino-9-deoxy cinchona alkaloid derivatives. Diastereoselectivities up 98% enantioselectivities 89% for a range of 5-aryl-1,3-dioxolan-4-ones under mild reaction conditions are reported.
Catalytic enantioselective tandem carbonyl ylide formation–cycloadditions of α-diazo-β-keto ester 1 using 0.5 mol% dirhodium tetrakis(1,1′-binaphthyl-2,2′-diyl phosphate) catalysts 7–9 and 14 to give the cycloadduct 3 in good yields up 90% ee are described.
Preventing entry of HIV into human host cells has emerged as an attractive approach to controlling viral replication. Maraviroc 1 is approved antagonist the CCR5 receptor which prevents HIV. Herein, we report design and discovery a series imidazopiperidine antagonists retain antiviral profile window over hERG activity maraviroc 1, combined with improved absorption profiles in rat dog. Furthermore, this compounds been shown against laboratory generated maraviroc-resistant HIV-1 strain,...
Abstract KAT6A is a lysine histone acetyltransferase (HAT) of the MYST family HATs. KAT6A, and its paralog KAT6B, have been shown to acetylate H3K23Ac regulate diverse biological processes, including transcription, cell-cycle progression, stem cell maintenance development. Molecular dysregulation has observed in several cancers, amplifications breast, lung, ovarian cancer along with oncogenic fusions AML. In breast cancer, amplified as part 8p11 amplicon 10-15% patient population, which...
JQ1 is a BET-bromodomain inhibitor that has immunomodulatory effects. However, the precise molecular mechanism targets to elicit changes in antibody production not understood. Our results show induces apoptosis, reduces cell proliferation, and as consequence, inhibits antibody-secreting differentiation. ChIP-sequencing reveals selective displacement of Brd4 response acute treatment (<2 h), resulting specific transcriptional repression. After 8 h, subsequent alterations gene expression arise...
Catalytic enantioselective tandem oxidopyrylium formation -intramolecular 1,3-dipolar cycloaddition reactions of phthalic anhydride-derived unsaturated diazocarbonyl compounds in up to 19% ee are described.
In this article, we describe the discovery of an aryl ether series potent and selective Nav1.3 inhibitors. Based on structural analogy to a similar compounds have previously shown bind domain IV voltage sensor region Nav channels, propose binds in same location. We development from published starting point, highlighting key selectivity potency data, several studies designed validate as target for pain.
The WD40-repeat protein WDR5 scaffolds various epigenetic writers and is a critical component of the mammalian SET/MLL histone methyltransferase complex. Dysregulation MLL1 catalytic function associated with mixed-lineage leukemia, antagonism WDR5-MLL1 interaction by small molecules has been proposed as therapeutic strategy for MLL-rearranged cancers. Small molecule binders “WIN” site that cause displacement from chromatin have additionally implicated to be broader use in cancer treatment....
A functionalisation of 1,3-diones using hypervalent iodine has been developed that is useful in the preparation libraries heterocyclic compounds.