A5023771680- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Ion channel regulation and function
- Cancer-related gene regulation
- Epigenetics and DNA Methylation
- Drug Transport and Resistance Mechanisms
- Pharmacological Effects and Toxicity Studies
- Histone Deacetylase Inhibitors Research
- Neuroscience and Neuropharmacology Research
- Quinazolinone synthesis and applications
- Protein Degradation and Inhibitors
- RNA modifications and cancer
- Synthetic Organic Chemistry Methods
- Nicotinic Acetylcholine Receptors Study
- Computational Drug Discovery Methods
- Biochemical and Molecular Research
- Pain Mechanisms and Treatments
- Microbial Natural Products and Biosynthesis
- Ubiquitin and proteasome pathways
- Asymmetric Synthesis and Catalysis
- HER2/EGFR in Cancer Research
- Carbohydrate Chemistry and Synthesis
- Protein Kinase Regulation and GTPase Signaling
- Nerve injury and regeneration
- Marine Sponges and Natural Products
AstraZeneca (United Kingdom)
2019-2024
AstraZeneca (United States)
2024
AstraZeneca (Singapore)
2020
Indian Institute of Technology Bombay
2020
University of Trieste
2020
University of Cagliari
2020
Pfizer (United Kingdom)
2008-2018
Pfizer (United States)
2011-2016
University of Oxford
2009
KRAS is an archetypal high-value intractable oncology drug target. The glycine to cysteine mutation at codon 12 represents Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based design approach led the identification of 21, AZD4625, a clinical development candidate for treatment KRASG12C positive tumors. Highlights include quinazoline tethering strategy lock out bio-relevant binding conformation and optimization focused on reduction...
NaV 1.8 ion channels have been highlighted as important molecular targets for the design of low MW blockers treatment chronic pain. Here, we describe effects PF-01247324, a new generation, selective, orally bioavailable Nav channel blocker novel chemotype.The inhibition by PF-01247324 was studied using in vitro patch-clamp electrophysiology and oral bioavailability antinociceptive demonstrated vivo rodent models inflammatory neuropathic pain.PF-01247324 inhibited native...
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...
Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRASG12C mutant represents an "Achilles heel" has recently yielded covalent targeting small molecules that bind cysteine create allosteric pocket on GDP-bound RAS, locking it in inactive state. A weak inhibitor at this site was optimized through conformational of a piperazine-quinazoline motif linker modification. Subsequent introduction key methyl...
Tropomyosin receptor kinases (TrkA, TrkB, TrkC) are activated by hormones of the neurotrophin family: nerve growth factor (NGF), brain derived neurotrophic (BDNF), 3 (NT3), and 4 (NT4). Moreover, NGF antibody tanezumab has provided clinical proof concept for inhibition TrkA kinase pathway in pain leading to significant interest development small molecule inhibitors TrkA. However, achieving subtype selectivity over TrkB TrkC via a Type I II inhibitor binding mode proven challenging III or IV...
The glycine to cysteine mutation at codon 12 of Kirsten rat sarcoma (KRAS) represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach led the identification 14, AZD4747, a clinical development candidate for treatment KRASG12C-positive tumors, including central nervous system (CNS) metastases. Building on earlier discovery C5-tethered quinazoline AZD4625, excision usually critical pyrimidine ring yielded weak...
The optimization of an allosteric fragment, discovered by differential scanning fluorimetry, to in vivo MAT2a tool inhibitor is discussed. structure-based drug discovery approach, aided relative binding free energy calculations, resulted AZ'9567 (21), a potent vitro with excellent preclinical pharmacokinetic properties. This showed selective antiproliferative effect on methylthioadenosine phosphorylase (MTAP) KO cells, both and vivo, providing further evidence support the utility inhibitors...
Optimization of ligand binding affinity to the target protein interest is a primary objective in small-molecule drug discovery. Until now, prediction affinities by computational methods has not been widely applied discovery process, mainly because its lack accuracy and reproducibility as well long turnaround times required obtain results. Herein we report on collaborative study that compares tropomyosin receptor kinase A (TrkA) predictions using two recently formulated fast approaches,...
MAT2a is a methionine adenosyltransferase that synthesizes the essential metabolite S-adenosylmethionine (SAM) from and ATP. Tumors bearing co-deletion of p16 MTAP genes have been shown to be sensitive inhibition, making it an attractive target for treatment MTAP-deleted cancers. A fragment-based lead generation campaign identified weak but efficient hits binding in known allosteric site. By use structure-guided design systematic SAR exploration, were elaborated through merging growing...
A reaction sequence involving the chemoselective olefinic oxidation of N(1)-benzyl-2,7-dihydro-1H-azepine with m-CPBA in presence HBF4 and BnOH followed by ring contraction facilitates stereoselective preparation either epoxide diastereoisomers (2RS,3SR)-N(1)-benzyl-2-chloromethyl-3-benzyloxy-4,5-epoxypiperidine simple modification conditions. Epoxide opening, functional group interconversion, deprotection allow synthesis (±)-1-deoxynojirimycin (±)-1-deoxyaltronojirimycin.
Voltage-gated sodium channels, in particular Nav1.8, can be targeted for the treatment of neuropathic and inflammatory pain. Herein, we described optimization Nav1.8 modulator series to deliver subtype selective, state, use-dependent chemical matter that is efficacious preclinical models
Hormones of the neurotrophin family, nerve growth factor (NGF), brain derived neurotrophic (BDNF), 3 (NT3), and 4 (NT4), are known to activate family Tropomyosin receptor kinases (TrkA, TrkB, TrkC). Moreover, inhibition TrkA kinase pathway in pain has been clinically validated by NGF antibody tanezumab, leading significant interest development small molecule inhibitors TrkA. Furthermore, Trk having an acceptable safety profile will require minimal availability. Herein, we discuss discovery...
Aberrant activity of the histone methyltransferase polycomb repressive complex 2 (PRC2) has been linked to several cancers, with small-molecule inhibitors catalytic subunit PRC2 enhancer zeste homologue (EZH2) being recently approved for treatment epithelioid sarcoma (ES) and follicular lymphoma (FL). Compounds binding EED have emerged as allosteric activity. In contrast orthosteric that target EZH2, small molecules bind retain their efficacy in EZH2 inhibitor-resistant cell lines. this...
Oxidation of enantiomerically pure (R)-N(1)-1'-(1''-naphthyl)ethyl-2,7-dihydro-1H-azepine with m-CPBA in the presence HBF(4) and BnOH gave (3S,4R,5S,6S,1'R)-N(1)-1'-(1''-naphthyl)ethyl-3-hydroxy-4-benzyloxy-5,6-epoxyazepane as major product a single diastereoisomer after chromatography. Elaboration this highly functionalized intermediate via ring contraction to (2S,3R,4S,5S,1'R)-N(1)-benzyl-2-chloromethyl-3-benzyloxy-4,5-epoxypiperidine followed by regioselective epoxide opening, functional...