A5069410524- Lung Cancer Treatments and Mutations
- Catalytic Cross-Coupling Reactions
- Synthetic Organic Chemistry Methods
- HER2/EGFR in Cancer Research
- Asymmetric Synthesis and Catalysis
- Cyclopropane Reaction Mechanisms
- Coordination Chemistry and Organometallics
- Quinazolinone synthesis and applications
- Synthesis and biological activity
- Cancer therapeutics and mechanisms
- Microwave-Assisted Synthesis and Applications
- Organoboron and organosilicon chemistry
- Advanced Synthetic Organic Chemistry
- Chemical synthesis and alkaloids
- PI3K/AKT/mTOR signaling in cancer
- N-Heterocyclic Carbenes in Organic and Inorganic Chemistry
- International Maritime Law Issues
- Down syndrome and intellectual disability research
- Wildlife Conservation and Criminology Analyses
- Synthesis and Reactions of Organic Compounds
- Organic Chemistry Cycloaddition Reactions
- X-ray Diffraction in Crystallography
- Lung Cancer Research Studies
- Marine and environmental studies
- Enzyme Structure and Function
AstraZeneca (United Kingdom)
2009-2017
John Innes Centre
2017
Durham University
2009-2014
AstraZeneca (Brazil)
2013
Surrey and Borders Partnership NHS Foundation Trust
2013
University College London
2002
University of Bath
1998
Approximately one-third of patients with non-small cell lung cancer (NSCLC) harboring tumors EGFR-tyrosine kinase inhibitor (TKI)-sensitizing mutations (EGFRm) experience disease progression during treatment due to brain metastases. Despite anecdotal reports EGFR-TKIs providing benefit in some EGFRm NSCLC metastases, there is a clinical need for novel improved efficacy against lesions.We performed preclinical assessments penetration and activity osimertinib (AZD9291), an oral, potent,...
Epidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a number years. Despite encouraging clinical efficacy with these agents, many resistance develops leading to disease progression. In most cases, this is form T790M mutation. addition, EGFR wild type inhibition inherent agents can lead dose limiting toxicities rash and diarrhea. We describe herein...
A novel series of small-molecule inhibitors has been developed to target the double mutant form epidermal growth factor receptor (EGFR) tyrosine kinase, which is resistant treatment with gefitinib and erlotinib. Our reported compounds also show selectivity over wild-type EGFR. Guided by molecular modeling, this was evolved a cysteine residue in ATP binding site via covalent bond formation demonstrates high levels activity cellular models In addition, these significant against activating...
Inhibition of the protein–protein interaction between B-cell lymphoma 6 (BCL6) and corepressors has been implicated as a therapeutic target in diffuse large (DLBCL) cancers profiling potent selective BCL6 inhibitors are critical to test this hypothesis. We identified pyrazolo[1,5-a]pyrimidine series binders from fragment screen parallel with virtual screen. Using structure-based drug design, binding affinity was increased 100000-fold. This involved displacing crystallographic water, forming...
A novel series of PAK1 inhibitors was discovered from a kinase directed screen. SAR exploration in the selectivity pocket and solvent tail regions conducted to understand optimise potency against targeted kinases. liganded crystal structure utilised guide compound design. Permeability impacted translation enzyme cellular potency. Compound 36 (AZ-PAK-36) demonstrated improved Gini coefficient, good has utility as tool for target validation studies.
People with learning disabilities are frequently denied or restricted in their right to express sexuality by restrictive policies, negative attitudes lack of awareness needs. They also tend have differing and unrecognised sexual health needs those the general population. Evidence suggests that acquiring a greater knowledge relationship issues helps decrease these disadvantages promote sense well-being for this group.The experiences eight adults attending group, based on mixture validated...
The generation of silenes through the rhodium-catalysed decomposition α-hypersilyl diazocarbonyl compounds has been explored both computationally and experimentally. This transformation proceeds via a pathway involving initial formation carbene, followed by rearrangement, initially to silene ultimately ketene. Density functional theory (DFT) calculations model suggested that was most preferential with electron donating substituents attached carbonyl group. predictions were experimentally...
Silenes, generated through thermolysis of acylpolysilanes, add to α,β-unsaturated esters form cyclobutanes and silylsubstituted cyclopropanes in moderate yields. Upon Si−C bond oxidation the are converted directly 1,4-dicarbonyl compounds, thus demonstrating formal acyl anion chemistry polysilanes.
A new synthetic route to 3-(heteroaryl) tetrahydropyrazolo[3,4-c]pyridines has been developed that uses the Suzuki–Miyaura cross-coupling of a triflate 6 with (hetero)aryl boronic acids or esters. Using Pd(OAc)2 and XPhos an precatalyst, diverse range substituents at C3 position tetrahydropyrazolo[3,4-c]pyridine skeleton were prepared. The use pivaloyloxymethyl benzyl protection also offers potential differentially functionalize pyrazole tetrahydropyridine nitrogens.
The synthesis of silaheterocycles through the first examples an intramolecular silene Diels–Alder reaction is described.
A range of useful disubstituted benzyl alcohol building blocks have been synthesised in multigram quantities a lithium–bromide exchange to give aldehyde, carboxylic acid and pinacol boranes high yields.
Abstract A derivative of (Ia) with a methyl‐substituent at the terminal double bond yields no cycloadduct under presented conditions.
Abstract AKT is a key node in the most frequently de-regulated signaling pathway human cancer and has been shown to mediate resistance range of cytotoxic, anti-hormonal targeted therapies. We decided explore inhibitors as potential new anti-cancer therapeutics. Here we disclose for first time discovery structure AZD5363, an orally bioavailable, potent ATP-competitive inhibitor AKT. evaluated chemical starting points arising from our previous collaboration with Institute Cancer Research Astex...