A5065879363- Chemical Synthesis and Analysis
- PI3K/AKT/mTOR signaling in cancer
- Cancer Mechanisms and Therapy
- Growth Hormone and Insulin-like Growth Factors
- Click Chemistry and Applications
- Hepatitis B Virus Studies
- Enzyme function and inhibition
- Metabolism, Diabetes, and Cancer
- Nuclear Receptors and Signaling
- Synthesis and biological activity
- Synthesis and Catalytic Reactions
- HER2/EGFR in Cancer Research
- Asymmetric Synthesis and Catalysis
- RNA modifications and cancer
- Drug Transport and Resistance Mechanisms
- Enzyme Structure and Function
- Chronic Myeloid Leukemia Treatments
- Free Radicals and Antioxidants
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- RNA Research and Splicing
- Mast cells and histamine
- Antibiotic Resistance in Bacteria
- Protein Kinase Regulation and GTPase Signaling
- Oxidative Organic Chemistry Reactions
- Viral gastroenteritis research and epidemiology
Ondine Biopharma (United States)
2024
Assembly Biosciences (United States)
2015
Stony Brook University
2015
Nationwide Children's Hospital
2011
ArmaGen (United States)
2010
Abbott Fund
2005-2007
Abbott (United States)
2004-2006
University of Alberta
1986-2003
Research Canada
1996
McGill University
1994-1995
Phosphorylation of tyrosine residues on the epidermal growth factor (EGF) receptor (EGFr) is an important early event in signal transduction, leading to cell replication for major human carcinomas. CP-358,774 a potent and selective inhibitor EGFr kinase produces inhibition EGF-mediated tumor mitogenesis. To assess pharmacodynamic aspects inhibition, we devised ex vivo enzyme-linked immunosorbent assay quantification EGFr-specific phosphorylation tissue specimens obtained from xenografts...
Background: The IGF-1 receptor (IGF-1R) has been implicated in the promotion of tumorigenesis, metastasis and resistance to cancer therapies. Therefore, this become a major focus for development anticancer agents. Results: Our lead optimization efforts that blended structure-based design empirical medicinal chemistry led discovery OSI-906, novel small-molecule dual IGF-1R/insulin (IR) kinase inhibitor. OSI-906 potently selectively inhibits autophosphorylation both human IGF-1R IR, displays...
Abstract The phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway is frequently activated in human cancers, and mTOR a clinically validated target. forms two distinct multiprotein complexes, mTORC1 mTORC2, which regulate cell growth, metabolism, proliferation, survival. Rapamycin its analogues partially inhibit through allosteric binding to mTORC1, but not have shown clinical utility certain cancers. Here, we report the preclinical characterization of OSI-027, selective potent dual inhibitor...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTConversion of serine to stereochemically pure .beta.-substituted .alpha.-amino acids via .beta.-lactonesLee D. Arnold, Thomas H. Kalantar, and John C. VederasCite this: J. Am. Chem. Soc. 1985, 107, 24, 7105–7109Publication Date (Print):November 1, 1985Publication History Published online1 May 2002Published inissue 1 November 1985https://pubs.acs.org/doi/10.1021/ja00310a058https://doi.org/10.1021/ja00310a058research-articleACS PublicationsRequest...
Insulin-like growth factor-I receptor (IGF-IR) and its ligands, IGF-I IGF-II, are up-regulated in a variety of human cancers. In tumors, such as colorectal, non-small cell lung, ovarian, pediatric cancers, which may drive their own survival through autocrine IGF-II expression, the role IGF-IR is especially critical. Here, we present novel small-molecule kinase inhibitor, cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine (PQIP),...
A series of novel thienopyrimidine-based receptor tyrosine kinase inhibitors has been discovered. Investigation structure-activity relationships at the 5- and 6-positions thienopyrimidine nucleus led to a N,N'-diaryl ureas that potently inhibit all vascular endothelial growth factor (VEGF) platelet-derived (PDGF) kinases. insert domain-containing (KDR) homology model suggests these compounds bind "inactive conformation" enzyme with urea portion extending into back hydrophobic pocket adjacent...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSynthesis of optically pure .alpha.-amino acids via salts .alpha.-amino-.beta.-propiolactoneLee D. Arnold, Robert G. May, and John Christopher. VederasCite this: J. Am. Chem. Soc. 1988, 110, 7, 2237–2241Publication Date (Print):March 1, 1988Publication History Published online1 May 2002Published inissue 1 March 1988https://pubs.acs.org/doi/10.1021/ja00215a038https://doi.org/10.1021/ja00215a038research-articleACS PublicationsRequest reuse...
The SET and MYND Domain (SMYD) proteins comprise a unique family of multi-domain histone methyltransferases that are implicated in human cancer progression. Here we report an analysis the crystal structure full length SMYD3 complex with analog S-adenosyl methionine (SAM) methyl donor cofactor. revealed overall compact architecture which “split-SET” domain adopts canonical fold closely assembles Zn-binding C-terminal superhelical 9 α-helical bundle similar to observed for mouse SMYD1...
Fibroblast growth factor receptor (FGFR) alterations are present as oncogenic drivers and bypass mechanisms in many forms of cancer. These can include fusions, amplifications, rearrangements, mutations. Acquired drug resistance to current FGFR inhibitors often results disease progression unfavorable outcomes for patients. Genomic profiling tumors refractory the clinic has revealed several acquired driver that could be target next generation therapeutics. Herein, we describe how...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTConversion of serine .beta.-lactones to chiral .alpha.-amino acids by copper-containing organolithium and organomagnesium reagentsLee D. Arnold, John C. G. Drover, VederasCite this: J. Am. Chem. Soc. 1987, 109, 15, 4649–4659Publication Date (Print):July 1, 1987Publication History Published online1 May 2002Published inissue 1 July 1987https://pubs.acs.org/doi/10.1021/ja00249a031https://doi.org/10.1021/ja00249a031research-articleACS...
Despite the existence of a preventive vaccine, chronic infection with Hepatitis B virus (HBV) affects more than 250 million people and represents major global cause hepatocellular carcinoma (HCC) worldwide. Current clinical treatments, in most cases, do not eliminate viral genome that persists as DNA episome nucleus hepatocytes constitutes stable template for continuous expression genes. Several studies suggest that, among factors, HBV core protein (HBc), well-known its structural role...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTPolymer-supported alkyl azodicarboxylates for Mitsunobu reactionsLee D. Arnold, Hanaa I. Assil, and John C. VederasCite this: J. Am. Chem. Soc. 1989, 111, 11, 3973–3976Publication Date (Print):May 1, 1989Publication History Published online1 May 2002Published inissue 1 1989https://pubs.acs.org/doi/10.1021/ja00193a032https://doi.org/10.1021/ja00193a032research-articleACS PublicationsRequest reuse permissionsArticle...
OSI-930 is a novel inhibitor of the receptor tyrosine kinases Kit and kinase insert domain (KDR), which currently being evaluated in clinical studies. selectively inhibits KDR with similar potency intact cells also these targets vivo following oral dosing. We have investigated relationships between observed cell-based assays vitro, plasma exposure levels achieved dosing, time course target inhibition vivo, antitumor activity tumor xenograft models. In mutant Kit-expressing HMC-1 model,...
Kinases are known to regulate fundamental processes in cancer including tumor proliferation, metastasis, neovascularization, and chemoresistance. Accordingly, kinase inhibitors have been a major focus of drug development, several now approved for various indications. Typically, selected via high-throughput screening using catalytic domains at low ATP concentration, this process often yields mimetics that lack specificity and/or function poorly cells where levels high. Molecules targeting the...
β-Tryptase, a homotetrameric serine protease, has four identical active sites facing central pore, presenting an optimized setting for the rational design of bivalent inhibitors that bridge two adjacent sites. Using diol, hydroxymethyl phenols or benzoyl methyl hydroxamates, and boronic acid chemistries to reversibly join [3-(1-acylpiperidin-4-yl)phenyl]methanamine core ligands, we have successfully produced series self-assembling heterodimeric inhibitors. These tryptase demonstrate superior...
The unprecedented scale of the COVID-19 pandemic and rapid evolution SARS-CoV-2 variants underscore need for broadly active inhibitors with a high barrier to resistance. coronavirus main protease (M
RAF, a core signaling component of the MAPK kinase cascade, is often mutated in various cancers, including melanoma, lung, and colorectal cancers. The approved inhibitors were focused on targeting BRAFV600E mutation that results constitutive activation through monomeric protein (Class I). However, these also paradoxically activate RAF dimers, resulting increased normal tissues. Recently, significant attention has turned to alterations dimeric (class II III BRAF NRAS). discovery potent...
Analogs 1-8 of diaminopimelic acid (DAP) were synthesized and tested for inhibition purified meso-DAP D-dehydrogenase from Bacillus sphaericus LL-DAP epimerase Escherichia coli. The dehydrogenase was assayed by monitoring NADPH formation spectrophotometrically at 340 nm. N-Hydroxy DAP 4, N-amino 5, 4-methylene 6 are substrates the with relative rates exceeding those meso isomers thia analogs 1ab, 2ab, 3ab. coupling epimerization to DL-DAP (Km = 0.26 mM) dehydrogenase-catalyzed oxidation...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTThe nitrogen of the acetamido group colchicine modulates P-glycoprotein-mediated multidrug resistanceDavid F. Tang-Wai, Arnold Brossi, Lee D. Arnold, and Philippe GrosCite this: Biochemistry 1993, 32, 25, 6470–6476Publication Date (Print):June 29, 1993Publication History Published online1 May 2002Published inissue 29 June 1993https://pubs.acs.org/doi/10.1021/bi00076a022https://doi.org/10.1021/bi00076a022research-articleACS PublicationsRequest reuse...
Analogs (146) of diaminopimelic acid have been synthesized and tested for inhibition meso-diaminopimelate decarboxylases from Bacillus sphaericus IF0 3525 wheat germ (Triticum vulgaris).Difluoromethyldiaminopimelate I does not irreversibly inactivate or strongly competitively inhibit either enzyme.Lanthlonine sulfoxides (2ab, 2c, 2d) are good competitive inhibitors (about 50% at 1 mM) both decarboxylases.The meso LL-isomers Ianthionine sulfone (3ab 3c) lanthionine (6ab 6c) weaker 10-20...
The synthesis of a novel series 1,4-dihydroindeno[1,2-c]pyrazoles with acetylene-type side chains is described. Optimization those compounds as KDR kinase inhibitors identified 8, which displayed an oral activity in estradiol-induced murine uterine edema model (ED50 = 3 mg/kg) superior to Sutent 9 and showed potent antitumor efficacy MX-1 human breast carcinoma xenograft tumor growth (tumor inhibition 90% at 25 mg/kg.day po). compound was docked into homology the homo-tetrameric pore domain...
We describe the successful application of a novel approach for generating dimeric Myc inhibitors by modifying and reversibly linking two previously described small molecules. synthesized directed libraries monomers, each comprised ligand, connector, bioorthogonal linker element, to identify optimal dimer configuration required inhibit Myc. identified combinations termed self-assembling inhibitors, which displayed synergistic inhibition Myc-dependent cell growth. confirmed that these directly...