A5019998609- Lung Cancer Treatments and Mutations
- Synthesis and Catalytic Reactions
- Cancer therapeutics and mechanisms
- Mast cells and histamine
- Immune cells in cancer
- HER2/EGFR in Cancer Research
- Cancer Research and Treatments
- Cancer, Stress, Anesthesia, and Immune Response
- Colorectal Cancer Treatments and Studies
- Tuberculosis Research and Epidemiology
- Cytokine Signaling Pathways and Interactions
- Chronic Myeloid Leukemia Treatments
- Quinazolinone synthesis and applications
- Synthetic Organic Chemistry Methods
- DNA Repair Mechanisms
- Chemical Synthesis and Analysis
- DNA and Nucleic Acid Chemistry
- Lung Cancer Research Studies
- Immune Cell Function and Interaction
- Cancer, Hypoxia, and Metabolism
- Gastric Cancer Management and Outcomes
- Chronic Lymphocytic Leukemia Research
- Marine Sponges and Natural Products
- Advanced Synthetic Organic Chemistry
- Biochemical and Molecular Research
AstraZeneca (United Kingdom)
2015-2024
AstraZeneca (Brazil)
2013
University of California, San Diego
1999-2000
Scripps Research Institute
1999
University of Cambridge
1996-1997
University of Salford
1995
CEA Grenoble
1983
First-generation EGFR tyrosine kinase inhibitors (EGFR TKI) provide significant clinical benefit in patients with advanced EGFR-mutant (EGFRm(+)) non-small cell lung cancer (NSCLC). Patients ultimately develop disease progression, often driven by acquisition of a second T790M TKI resistance mutation. AZD9291 is novel oral, potent, and selective third-generation irreversible inhibitor both EGFRm(+) sensitizing mutants that spares wild-type EGFR. This mono-anilino-pyrimidine compound...
An interactive protein secondary structure prediction Internet server is presented. The allows a single sequence or multiple alignment to be submitted, and returns predictions from six algorithms that exploit evolutionary information sequences. A consensus also returned which improves the average Q3 accuracy of by 1% 72.9%. simplifies use current conservation patterns important function identified.http://barton.ebi.ac.uk/servers/jpred.h tmlgeoff@ebi.ac.uk
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...
DNA-dependent protein kinase (DNA-PK) is a critical player in the DNA damage response (DDR) and instrumental non-homologous end-joining pathway (NHEJ) used to detect repair double-strand breaks (DSBs). We demonstrate that potent highly selective DNA-PK inhibitor, AZD7648, an efficient sensitizer of radiation- doxorubicin-induced damage, with combinations xenograft patient-derived (PDX) models inducing sustained regressions. Using ATM-deficient cells, we combination PARP inhibitor olaparib,...
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...
Abstract Purpose: Osimertinib is a potent and selective EGFR tyrosine kinase inhibitor (EGFR-TKI) of both sensitizing T790M resistance mutations. To treat metastatic brain disease, blood–brain barrier (BBB) permeability considered desirable for increasing clinical efficacy. Experimental Design: We examined the level penetration 16 irreversible reversible EGFR-TKIs using multiple in vitro vivo BBB preclinical models. Results: In osimertinib was weakest substrate human efflux transporters...
Constitutively active mutant KRas displays a reduced rate of GTP hydrolysis via both intrinsic and GTPase-activating protein-catalyzed mechanisms, resulting in the perpetual activation Ras pathways. We describe fragment screening campaign using X-ray crystallography that led to discovery three binding sites on Ras:SOS complex. The identification tool compounds at each these allowed exploration two new approaches pathway inhibition by stabilizing or covalently modifying complex prevent...
Abstract EGFR exon 20 insertions (Ex20Ins) account for 4% to 10% of activating mutations in non–small cell lung cancer (NSCLC). Ex20Ins tumors are generally unresponsive first- and second-generation inhibitors, current standard care NSCLC patients with is conventional cytotoxic chemotherapy. Therefore, the development an TKI that can more effectively target represents a major advance this patient subset. Osimertinib third-generation approved treatment advanced harboring T790M; however,...
DNA-PK is a key component within the DNA damage response, as it responsible for recognizing and repairing double-strand breaks (DSBs) via non-homologous end joining. Historically has been challenging to identify inhibitors of catalytic subunit (DNA-PKcs) with good selectivity versus structurally related PI3 (lipid) PI3K-related protein kinases. We screened our corporate collection DNA-PKcs kinase selectivity, identifying compound 1. Optimization focused on further improving while physical...
Potentiating radiotherapy and chemotherapy by inhibiting DNA damage repair is proposed as a therapeutic strategy to improve outcomes for patients with solid tumors. However, this approach risks enhancing normal tissue toxicity much tumor toxicity, thereby limiting its translational impact. Using NU5455, newly identified highly selective oral inhibitor of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) activity, we found that it was indeed possible preferentially augment the effect...
The epidermal growth factor receptor (EGFR) harboring activating mutations is a clinically validated target in non-small-cell lung cancer, and number of inhibitors the EGFR tyrosine kinase domain, including osimertinib, have been approved for clinical use. Resistance to these therapies has emerged due variety molecular events C797S mutation which renders third-generation C797-targeting covalent considerably less potent against loss key covalent-bond-forming residue. We describe medicinal...
The macrolactonization-based strategy for the total synthesis of epothilones has been streamlined and improved to a high level efficiency stereoselectivity. This applied construction vinyl iodide 19 which served as common intermediate series natural designed including an epothilone B10 (3), F (5), 16-desmethylepothilone B (14), pyridine 57a-57g, dimeric 59 61, benzenoid 63a-63g.
High throughput screening followed by a lead generation campaign uncovered novel series of urea containing morpholinopyrimidine compounds which act as potent and selective dual inhibitors mTORC1 mTORC2. We describe the continued compound optimization for this series, in particular focused on identifying with improved cellular potency, aqueous solubility, good stability human hepatocyte incubations. Knowledge from empirical SAR investigations was combined an understanding molecular...
Tumors have evolved a variety of methods to reprogram conventional metabolic pathways favor their own nutritional needs, including glutaminolysis, the first step which is hydrolysis glutamine glutamate by amidohydrolase glutaminase 1 (GLS1). A GLS1 inhibitor could potentially target certain cancers blocking tumor cell's ability produce glutamine-derived nutrients. Starting from known bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide, we describe medicinal chemistry evolution...
Arginase has long been a target of interest in immuno-oncology, but discovering an orally bioavailable inhibitor is severely constrained by the requisite boronic acid pharmacophore. We began our drug discovery campaign building off β-position literature ABH (
Arginase is a promising immuno-oncology target that can restore the innate immune response. However, it's highly polar active site often requires potent inhibitors to mimic amino acids, leading poor passive permeability and low oral exposure. Using structure-based drug design, we discovered novel proline-based arginase inhibitor (