Search

Your search keyword '"A kinase"' showing total 4 results
Start Over Descriptor "A kinase" Journal bioorganicmedicinal chemistry letters
4 results on '"A kinase"'

1. Discovery of small molecule FLT3 inhibitors that are able to overcome drug-resistant mutations

Author

Shusheng Lai, Lin-Li Li, Tianqi Wang, Ming Chen, Jinshan Nan, Guo Zhang, Bolin Li, Wenqing Zhang, Yifei Wang, Chenjian Shen, Jie-Min Zhong, and Shengyong Yang

Subjects
Clinical Biochemistry, Pharmaceutical Science, Drug resistance, 01 natural sciences, Biochemistry, Small Molecule Libraries, chemistry.chemical_compound, Structure-Activity Relationship, Cell Line, Tumor, Drug Discovery, Structure–activity relationship, Humans, Urea, Molecular Biology, Protein Kinase Inhibitors, Dose-Response Relationship, Drug, Molecular Structure, 010405 organic chemistry, Chemistry, Organic Chemistry, Small molecule, Molecular biology, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, fms-Like Tyrosine Kinase 3, Drug Resistance, Neoplasm, Mutation, Molecular Medicine, Urea derivatives, A kinase, Selectivity, Lead compound
Abstract

Herein we report the discovery of 1-(5-(tert-butyl)isoxazol-3-yl)-3- (3-fluorophenyl)urea derivatives as new FLT3 inhibitors that are able to overcome the drug resistance mutations: the secondary D835Y and F691L mutations on the basis of the internal tandem duplications (ITD) mutation of FLT3 (FLT3-ITD/D835Y and FLT3-ITD/F691L, respectively). The most potent compound corresponds to 1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3- fluorophenyl)urea (4d), which showed IC50s (half maximal inhibitory concentrations) of 0.072 nM, 5.86 nM and 3.48 nM against FLT3-ITD, FLT3-ITD/F691L and FLT3-ITD/D835Y, respectively. Compound 4d also showed good selectivity for FLT3 in a kinase profiling assay. Collectively, 4d could be a good lead compound and deserves further in-depth studies.

Published
2020

2. 'Turn On/Off' fluorescence probe for the screening of unactivated Bruton's tyrosine kinase

Author

Wataru Kawahata, Ikuo Fujii, Tokiko Asami, and Masaaki Sawa

Subjects
biology, Chemistry, Btk inhibitors, Ligand binding assay, Organic Chemistry, Clinical Biochemistry, Pharmaceutical Science, Protein-Tyrosine Kinases, Biochemistry, Fluorescence, Molecular biology, Turn (biochemistry), immune system diseases, hemic and lymphatic diseases, Drug Discovery, biology.protein, Agammaglobulinaemia Tyrosine Kinase, Molecular Medicine, Bruton's tyrosine kinase, A kinase, Molecular Biology, Protein Kinase Inhibitors, Fluorescent Dyes
Abstract

BTK has emerged as a promising target for treating B-cell malignancies and autoimmune diseases, and there has been a growing demand to identify selective BTK inhibitors efficiently. In this Letter, we have designed and synthesized a new fluorescent probe to screen compounds that preferentially bind to an unactivated state of BTK (BTK [U]). The fluorescence of the probe was turned on in the presence of BTK [U], and quenched by the addition of compounds which preferentially bind to BTK [U]. This unique fluorescent probe was successfully applied to the screening of a kinase focused compound library. The results suggest that this new method is a simple and easy-to-perform assay to screen inhibitors of BTK [U].

Published
2015

3. SAR studies around a series of triazolopyridines as potent and selective PI3Kγ inhibitors

Author

Warren Miller, Giovanna Bergamini, Mihiro Sunose, Jess Taylor, Gitte Neubauer, Andrew Cansfield, Nigel Ramsden, Katie Ellard, and Kathryn Bell

Subjects
Stereochemistry, Pyridines, Clinical Biochemistry, Pharmaceutical Science, Administration, Oral, Biochemistry, Mice, Structure-Activity Relationship, Cell Line, Tumor, Microsomes, Drug Discovery, Animals, Class Ib Phosphatidylinositol 3-Kinase, Humans, Protein Isoforms, Kinome, Computer Simulation, Molecular Biology, Phosphoinositide-3 Kinase Inhibitors, Binding Sites, Chemistry, Arthritis, Organic Chemistry, Key features, Protein Structure, Tertiary, Rats, Disease Models, Animal, Molecular Medicine, Triazolopyridine, A kinase, Selectivity, Collagen-induced arthritis, Half-Life
Abstract

Herein we describe the SAR of a novel series of 6-aryl-2-amino-triazolopyridines as potent and selective PI3Kγ inhibitors. The 6-aryl-triazolopyridine core was identified by chemoproteomic screening of a kinase focused library. Rapid chemical expansion around a bi-functional core identified the key features required for PI3Kγ activity and selectivity. The series was optimized to afford 43 (CZC19945), a potent PI3Kγ inhibitor with high oral bioavailability and selectivity over PI3Kα and PI3Kδ. Modification to the core afforded 53 (CZC24832) which showed increased selectivity over the entire kinome in particular over PI3Kβ.

Published
2012

4. A rapid method for generation of selective Sox-based chemosensors of Ser/Thr kinases using combinatorial peptide libraries

Author

Juan A. González-Vera, Barbara Imperiali, and Elvedin Lukovic

Subjects
Clinical Biochemistry, Aurora A kinase, Pharmaceutical Science, Peptide, Protein Serine-Threonine Kinases, Biochemistry, Catalysis, Article, Aurora Kinases, Peptide Library, Drug Discovery, Combinatorial Chemistry Techniques, Peptide library, Molecular Biology, Fluorescent Dyes, chemistry.chemical_classification, Protein-Serine-Threonine Kinases, Kinase, Organic Chemistry, Substrate (chemistry), chemistry, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Molecular Medicine, A kinase
Abstract

A novel screening method to identify selective Sox-based fluorescent probes for Ser/Thr kinases has been developed. Peptide libraries were exposed to a kinase of interest and the products of the timed reaction were analyzed by MALDI-TOF. To demonstrate the potential of this methodology, a selective substrate for Aurora A kinase was identified that showed a 7-fold improvement in catalytic efficiency over the best substrate described to date in the literature.

Published
2008

Catalog

Books, media, physical & digital resources
See catalog results