A5049751354- Synthetic Organic Chemistry Methods
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Chemical Synthesis and Analysis
- Tryptophan and brain disorders
- Asymmetric Synthesis and Catalysis
- Histone Deacetylase Inhibitors Research
- Protein Degradation and Inhibitors
- Chemical synthesis and alkaloids
- Cyclopropane Reaction Mechanisms
- Click Chemistry and Applications
- Fluorine in Organic Chemistry
- Epigenetics and DNA Methylation
- Pharmacological Receptor Mechanisms and Effects
- Protein Kinase Regulation and GTPase Signaling
- Advanced Synthetic Organic Chemistry
- Immune cells in cancer
- 14-3-3 protein interactions
- Synthesis and Reactions of Organic Compounds
- Natural Compound Pharmacology Studies
- Adenosine and Purinergic Signaling
- Cancer-related gene regulation
- Peptidase Inhibition and Analysis
- Biochemical and Molecular Research
- Synthesis and pharmacology of benzodiazepine derivatives
Merck & Co., Inc., Rahway, NJ, USA (United States)
2009-2024
The Royal Free Hospital
2014
University College London
2014
Boston University
2011-2013
RMIT University
1996
RMIT Europe
1996
The bicyclo[1.1.1]pentane (BCP) motif has been utilized as bioisosteres in drug candidates to replace phenyl, tert-butyl, and alkynyl fragments order improve physicochemical properties. However, bceause of the difficulty synthesis, most BCP analogues prepared only bear 1,3-"para"-substituents. We report first selective synthesis 2,2-difluorobicyclo[1.1.1]pentanes via difluorocarbene insertion into bicyclo[1.1.0]butanes. Moreover, this methodology should inspire future studies on other...
Oncogenic mutations in the
Kibdelones are hexacyclic tetrahydroxanthones and potent anticancer agents isolated from an Australian microbe. Herein, we describe the synthesis of a chiral, nonracemic iodocyclohexene carboxylate EF ring fragment kibdelones employing intramolecular iodo halo-Michael aldol reaction its merger with ABCD to afford congener kibdelone C.
Indoleamine-2,3-dioxygenase 1 (IDO1) inhibition and its combination with immune checkpoint inhibitors like pembrolizumab have drawn considerable attention from both academia the pharmaceutical industry. Here, we describe discovery of a novel class highly potent IDO1 heme-displacing featuring unique bicyclo[1.1.1]pentane motif. Compound 1, evolving an ALIS (automated ligand identification system) hit, exhibited excellent potency but lacked desired pharmacokinetic profile due to extensive...
Prostaglandin E2 (PGE2), an arachidonic acid pathway metabolite produced by cyclooxygenase (COX)-1/2, has been shown to impair anti-tumor immunity through engagement with one or more E-type prostanoid receptors (EP1-4). Specific targeting of EP receptors, as opposed COX-1/2 inhibition, proposed achieve preferential antagonism PGE2–mediated immune suppression. Here we describe the activity MF-766, a potent and highly selective small-molecule inhibitor EP4 receptor. inhibition MF-766...
Arylation goes platinum: The synthesis of the ABCD ring fragments kibdelones has been achieved through a novel PtIV-catalyzed arylation quinone monoketal followed by photocyclization (see scheme). Biological evaluation in NCI 60-cell screen revealed that kibdelone analogues were about 2000 times less active than B and C, suggesting tetrahydroxanthone structure is crucial for cytotoxicity.
Protein arginine methyltransferase 5 (PRMT5) is a type II that catalyzes the post-translational symmetric dimethylation of protein substrates. PRMT5 plays critical role in regulating biological processes including transcription, cell cycle progression, RNA splicing, and DNA repair. As such, dysregulation activity implicated development progression multiple cancers target growing clinical interest. Described herein are structure-based drug designs, robust synthetic efforts, lead optimization...
Bicyclo[1.1.1]pentanes (BCP's) have been applied in medicinal chemistry as bioisosteres for phenyl groups. In pursuit of novel BCP analogs, we reported the first synthesis 2,2‐difluorobicyclo[1.1.1]pentanes (BCP–F 2 ) 2019. Herein, detail extension our effort BCP‐F analogs.
The action of arginase, a metalloenzyme responsible for the hydrolysis arginine to urea and ornithine, is hypothesized suppress immune-cell activity within tumor microenvironment, thus its inhibition may constitute means by which potentiate efficacy immunotherapeutics such as anti-PD-1 checkpoint inhibitors. Taking inspiration from reported enzyme–inhibitor cocrystal structures, we designed synthesized novel inhibitors human arginase possessing fused 5,5-bicyclic ring system. prototypical...
Cofactor mimicry represents an attractive strategy for the development of enzyme inhibitors but can lead to off-target effects due evolutionary conservation binding sites across proteome. Here, we uncover ADP-ribose (ADPr) hydrolase NUDT5 as unexpected, noncovalent, clinical BTK inhibitors. Using a combination biochemical, biophysical, and intact cell NanoBRET assays well X-ray crystallography, confirm catalytic inhibition cellular target engagement reveal unusual mode that is independent...
Recent data suggest that the inhibition of arginase (ARG) has therapeutic potential for treatment a number indications ranging from pulmonary and vascular disease to cancer. Thus, high demand exists selective small molecule ARG inhibitors with favorable druglike properties good oral bioavailability. In light significant challenges associated unique physicochemical previously disclosed inhibitors, we use structure-based drug design combined focused optimization strategy discover class boronic...
3,3-Disubstituted oxetanes have been utilized as bioisosteres for gem-dimethyl and cyclobutane functionalities. We report the discovery of a novel class oxetane indole-amine 2,3-dioxygenase (IDO1) inhibitors suitable Q3W (once every 3 weeks) oral parenteral dosing. A diamide IDO was discovered through an automated ligand identification system (ALIS). Installation fluorophenyl dramatically improved potency. Identification biaryl moiety unconventional amide isostere addressed metabolic...
Comprehensive synthetic strategies afforded a diverse set of structurally unique bicyclic proline-containing arginase inhibitors with high degree three-dimensionality. The analogs that favored the Cγ-exo conformation proline improved potency over initial lead. novel reported here not only enable access to previously unknown stereochemically complex derivatives but also provide foundation for future synthesis analogs, which incorporate inherent three-dimensional character into building...
Arylierungen jetzt auch mit Platin: Die Synthese des Titelsystems gelang durch eine neuartige PtIV-katalysierte Arylierung eines Chinonmonoketals und anschließende Photocyclisierung (siehe Schema). Nach ersten biologischen Tests an Krebszelllinien sind die verkürzten Kibdelon-Analoga rund 2000-mal weniger aktiv als Kibdelone B C, was darauf hinweist, dass Tetrahydroxanthonstruktur der entscheidend für Zytotoxizität ist. Detailed facts of importance to specialist readers are published as...
A new conservative Victorian state government has adopted, and extended, overseas privatisation approaches for resourcing managing human services. In some localities, these are destroying the infrastructure of community Without a dynamic services sector, opportunities social citizenship will remain elusive. This outcome parallels other Government actions that deny longstanding rights to political citizenship.
Mutant isocitrate dehydrogenase 1 (IDH1) has been identified as an attractive oncology target for which >70% of grade II and III gliomas ∼10% acute myeloid leukemia (AML) harbor somatic IDH1 mutations. These mutations confer a neomorphic gain function, leading to the production oncometabolite (R)-2-hydroxyglutarate (2-HG). We developed potent, selective, orally bioavailable brain-penetrant tricyclic diazepine scaffold that inhibits mutant IDH1. During course in vitro metabolism studies,...
Abstract KRAS mutations are the predominant oncogenic drivers in multiple indications including non-small cell lung carcinoma (NSCLC), colorectal (CRC) and pancreatic ductal adenocarcinoma (PDAC). has long been considered a challenging target due to perceived lack of druggable binding pockets high flexibility protein. However, recent progress discovering developing covalent inhibitors against GDP-loaded form G12C mutant provided strategy for targeting mutant-specific as cysteine residue...