A5016791761- Protein Degradation and Inhibitors
- Cytokine Signaling Pathways and Interactions
- Cancer Mechanisms and Therapy
- Multiple Myeloma Research and Treatments
- Computational Drug Discovery Methods
- Lung Cancer Treatments and Mutations
- Protein Kinase Regulation and GTPase Signaling
- Click Chemistry and Applications
- PARP inhibition in cancer therapy
- Cancer Immunotherapy and Biomarkers
- Histone Deacetylase Inhibitors Research
- Cancer-related Molecular Pathways
- DNA Repair Mechanisms
- Cancer therapeutics and mechanisms
- Phytochemistry and biological activities of Ficus species
- DNA and Nucleic Acid Chemistry
- Melanoma and MAPK Pathways
- Synthesis and biological activity
- Protein Structure and Dynamics
- HER2/EGFR in Cancer Research
- Adenosine and Purinergic Signaling
- Peptidase Inhibition and Analysis
- Cancer Genomics and Diagnostics
- Advanced biosensing and bioanalysis techniques
- Cancer-related gene regulation
AstraZeneca (United States)
2011-2022
AstraZeneca (Singapore)
2018
Kala Pharmaceuticals (United States)
2013-2017
AstraZeneca (United Kingdom)
2002-2017
Array BioPharma (United States)
2008
AstraZeneca (Brazil)
2007
AstraZeneca (Sweden)
2005
University of Oxford
1994-2000
Harvard University
1999-2000
University of Bristol
2000
The ability of molecular docking, using the program Glide and an MM-GBSA postdocking scoring protocol, to correctly rank a number congeneric kinase inhibitors was assessed. approach successful for cases considered suggests that this may be useful design in lead optimization phase drug discovery.
<h3>Background</h3> The Janus kinase (JAK) and signal transduction activation of transcription (STAT) signaling pathway is an attractive target in multiple cancers. Activation the JAK-STAT important both tumorigenesis immune responses. In diffuse large B-cell lymphoma (DLBCL), factor STAT3 has been associated with aggressive disease phenotype worse overall survival. While therapies inhibit upstream signaling, there limited success selectively targeting patients. Antisense oligonucleotides...
Four of the most well-known, commercially available docking programs, FlexX, GOLD, GLIDE, and ICM, have been examined for their ligand-docking virtual-screening capabilities. The relative performance programs in reproducing native ligand conformation from starting SMILES strings 164 high-resolution protein-ligand complexes is presented compared. Applying only scoring functions, latest versions these four were also used to conduct virtual screening 12 protein targets therapeutic interest,...
Activating mutations in KRAS underlie the pathogenesis of up to 20% human tumors, and is one most frequently mutated genes cancer. Developing therapeutics block activity has proven difficult, no direct inhibitor function entered clinical trials. We describe preclinical evaluation AZD4785, a high-affinity constrained ethyl-containing therapeutic antisense oligonucleotide (ASO) targeting mRNA. AZD4785 potently selectively depleted cellular mRNA protein, resulting inhibition downstream effector...
The bromodomain and extraterminal (BET) protein BRD4 regulates gene expression via recruitment of transcriptional regulatory complexes to acetylated chromatin. Pharmacological targeting bromodomains by small molecule inhibitors has proven be an effective means disrupt aberrant programs critical for tumor growth and/or survival. Herein, we report AZD5153, a potent, selective, orally available BET/BRD4 inhibitor possessing bivalent binding mode. Unlike previously described monovalent...
Background The Regulatory T cell (Treg) lineage is defined by the transcription factor FOXP3, which controls immune-suppressive gene expression profiles. Tregs are often recruited in high frequencies to tumor microenvironment where they can suppress antitumor immunity. We hypothesized that pharmacological inhibition of FOXP3 systemically delivered, unformulated constrained ethyl-modified antisense oligonucleotides could modulate activity and augment immunity providing therapeutic benefit...
A hybrid quantum mechanical−molecular mechanical (QM−MM) potential energy function with ab initio and density functional capabilities has been implemented in the CHARMM program. It makes use of program CADPAC molecular mechanics function; a GAMESS(US) interface to was already available. To test methodology, series relatively small systems are studied comparisons made full QM calculations those from various QM−MM partitions. Both Hartree−Fock for region presented and, where possible, compared...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTInsights into Chorismate Mutase Catalysis from a Combined QM/MM Simulation of the Enzyme ReactionPaul D. Lyne, Adrian J. Mulholland, and W. Graham RichardsCite this: Am. Chem. Soc. 1995, 117, 45, 11345–11350Publication Date (Print):November 1, 1995Publication History Published online1 May 2002Published inissue 1 November 1995https://doi.org/10.1021/ja00150a037Request reuse permissionsArticle Views557Altmetric-Citations139LEARN ABOUT THESE...
Self-organizing molecular field analysis (SOMFA) is a novel technique for three-dimensional quantitative structure−activity relations (3D-QSAR). It simple and intuitive in concept avoids the complex statistical tools variable selection procedures favored by other methods. Our calculations show method to be as predictive best 3D-QSAR methods available. Importantly, steric electrostatic maps can produced aid design process highlighting important features. The simplicity of leaves scope further...
ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTAb Initio QM/MM Study of the Citrate Synthase Mechanism. A Low-Barrier Hydrogen Bond Is not InvolvedAdrian J. Mulholland, Paul D. Lyne, and Martin KarplusView Author Information Department Chemistry Chemical Biology Harvard University, Cambridge, Massachusetts 02138 School Chemistry, University Bristol BS8 1TS, UK Cite this: Am. Chem. Soc. 2000, 122, 3, 534–535Publication Date (Web):January 8, 2000Publication History Received26 July...
A virtual screen of a subsection the AstraZeneca compound collection was performed for checkpoint kinase-1 (Chk-1 kinase) using knowledge-based strategy. This involved initial filtering by application generic physical properties followed removal compounds with undesirable chemical functionality. Subsequently, 3-D pharmacophore kinase binding motifs applied. database approximately 200K remained docking into active site Chk-1 kinase, FlexX-Pharm program. For each that docked successfully site,...
Checkpoint kinases CHK1 and CHK2 are activated in response to DNA damage that results cell cycle arrest, allowing sufficient time for repair. Agents lead abrogation of such checkpoints have potential increase the efficacy compounds as chemo- radiotherapies. Thiophenecarboxamide ureas (TCUs) were identified inhibitors by high throughput screening. A structure-based approach is described using crystal structures JNK1 complex with 1 2 CHK1-3b complex. The ribose binding pocket was targeted...
BRD4 is a transcriptional co-activator functioning to recruit regulatory complexes acetylated chromatin. A subset of High-grade Serous Ovarian Cancer (HGSOC) patients are typified by focal, recurrent gene amplifications. Despite previously described cancer dependencies, it unclear whether amplification events oncogenic in HGSOC. We find that physiologically relevant levels expression isoforms non-transformed ovarian cells result cellular transformation. Transcriptional profiling...
The Wnt pathway is an evolutionarily conserved and tightly regulated signaling network with important roles in embryonic development adult tissue regeneration. Impaired regulation, arising from mutations components, such as Axin, APC, β-catenin, results uncontrolled cell growth triggers oncogenesis. To explore the reported link between CK2 kinase activity signaling, we sought to identify a potent, selective inhibitor of suitable for proof concept studies vivo. Starting...
JAK1, JAK2, JAK3, and TYK2 belong to the JAK (Janus kinase) family. They play critical roles in cytokine signaling. Constitutive activation of JAK/STAT pathways is associated with a wide variety diseases. Particularly, pSTAT3 observed response treatment inhibitors oncogenic signaling such as EGFR, MAPK, AKT resistance or poorer agents targeting these pathways. Among family kinases, JAK1 has been shown be primary driver STAT3 phosphorylation signaling; therefore, selective inhibition can...
The design, synthesis and biological evaluation of a series 4-aminopyrazolylpyrimidines as potent Trk kinase inhibitors is reported. High-throughput screening identified promising hit in the 4-aminopyrazolylpyrimidine chemotype. Initial optimization led to more inhibitors. Further using two strategies resulted significant improvement physical properties discovery 10z (AZ-23), potent, orally bioavailable A/B inhibitor. compound offers potential test hypothesis that modulation activity will be...
In this letter, we describe the design, synthesis, and structure-activity relationship of 5-anilinopyrazolo[1,5-a]pyrimidine inhibitors CK2 kinase. Property-based optimization early leads using 7-oxetan-3-yl amino group led to a series matched molecular pairs with lower lipophilicity, decreased affinity for human plasma proteins, reduced binding hERG ion channel. Agents in study were shown modulate pAKT(S129), direct substrate CK2, vitro vivo, exhibited tumor growth inhibition when...
: PARP proteins represent a class of post-translational modification enzymes with diverse cellular functions. Targeting PARPs has proven to be efficacious clinically, but exploration the therapeutic potential inhibition been limited targeting poly(ADP-ribose) generating PARP, including PARP1/2/3 and tankyrases. The cancer-related functions mono(ADP-ribose) PARP6, remain largely uncharacterized. Here, we report novel strategy PARP6 using first reported inhibitors. By screening collection...
In this paper we describe a series of 3-cyano-5-aryl-7-aminopyrazolo[1,5-a]pyrimidine hits identified by kinase-focused subset screening as starting points for the structure-based design conformationally constrained 6-acetamido-indole inhibitors CK2. The synthesis, SAR, and effects novel on Akt signaling cell proliferation in vitro are described.
Trk receptor tyrosine kinases have been implicated in cancer and pain. A crystal structure of TrkA with AZ-23 (1a) was obtained, scaffold hopping resulted two 5/6-bicyclic series comprising either imidazo[4,5-b]pyridines or purines. Further optimization these fusion led to compounds subnanomolar potencies against kinase cellular assays. Antitumor effects a TrkA-driven mouse allograft model were demonstrated 2d 3a.