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Start Over Descriptor "kinase inhibitor design" Topic 01 natural sciences
4 results on '"kinase inhibitor design"'

1. New insights into 4-anilinoquinazolines as inhibitors of cardiac troponin I-interacting kinase (TNNI3K)

Author

Christopher R. M. Asquith, Carrow I. Wells, Graham J. Tizzard, William J. Zuercher, and Tuomo Laitinen

Subjects
4-anilino-quinazolines, conformational flexibility, Cardiac troponin, Pharmaceutical Science, Negative control, Protein Serine-Threonine Kinases, kinase inhibitor design, 01 natural sciences, Analytical Chemistry, lcsh:QD241-441, 03 medical and health sciences, chemistry.chemical_compound, lcsh:Organic chemistry, Drug Discovery, Quinazoline, Humans, Myocytes, Cardiac, Physical and Theoretical Chemistry, Kinase activity, Protein Kinase Inhibitors, 030304 developmental biology, 0303 health sciences, Aniline Compounds, 010405 organic chemistry, Kinase, Communication, Troponin I, Organic Chemistry, Small molecule, 0104 chemical sciences, Biochemistry, chemistry, Chemistry (miscellaneous), Quinazolines, Molecular Medicine, CARDIAC TROPONIN I-INTERACTING KINASE, cardiac troponin I–interacting kinase (TNNi3K), hinge binder, Methyl group
Abstract

We report the synthesis of several related 4-anilinoquinazolines as inhibitors of cardiac troponin I–interacting kinase (TNNi3K). These close structural analogs of 3-((6,7-dimethoxyquinazolin-4-yl)amino)-4-(dimethylamino)-N-methylbenzenesulfonamide (GSK114) provide new understanding of structure–activity relationships between the 4-anilinoquinazoline scaffold and TNNi3K inhibition. Through a small focused library of inhibitors, we observed that the N-methylbenzenesulfonamide was driving the potency in addition to the more traditional quinazoline hinge-binding motif. We also identified a compound devoid of TNNi3K kinase activity due to the addition of a methyl group in the hinge binding region. This compound could serve as a negative control in the study of TNNi3K biology. Small molecule crystal structures of several quinazolines have been solved, supporting observations made about overall conformation and TNNi3K inhibition.

Published
2020

2. 6-Bromo-N-(2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)quinolin-4-amine

Author

Graham J. Tizzard and Christopher R. M. Asquith

Subjects
conformational flexibility, 010405 organic chemistry, Stereochemistry, Chemistry, Organic Chemistry, Crystal structure, 010402 general chemistry, 01 natural sciences, Biochemistry, Small molecule, kinase inhibitor design, lcsh:QD146-197, 0104 chemical sciences, D-1, 4-anilino-quin(az)olines, 2-methyl-2h-1,2,3-triazole, Mass spectrum, lcsh:Inorganic chemistry, Amine gas treating, Physical and Theoretical Chemistry, hinge binder
Abstract

We describe a straightforward synthesis of the title compound, incorporating a relatively rare 2-methyl-2H-1,2,3-triazole heterocylic motif as a potential kinase inhibitor motif. The small molecule crystal structure has been resolved, revealing an interesting packing arrangement and overall conformation. We also performed routine characterization with 1H/13C-NMR and liquid chromatography (LC) and high-resolution mass spectra (HRMS).

Published
2019

3. 6-Bromo-N-(3-(difluoromethyl)phenyl)quinolin-4-amine

Author

Graham J. Tizzard and Christopher R. M. Asquith

Subjects
conformational flexibility, chemistry.chemical_classification, 010405 organic chemistry, Chemistry, Organic Chemistry, Salt (chemistry), Crystal structure, Ring (chemistry), kinase inhibitor design, 01 natural sciences, Biochemistry, Medicinal chemistry, Small molecule, lcsh:QD146-197, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, chemistry.chemical_compound, Aniline, 4-anilino-quin(az)olines, lcsh:Inorganic chemistry, Mass spectrum, Molecule, Amine gas treating, Physical and Theoretical Chemistry, hinge binder
Abstract

A routine synthesis was performed to furnish the title compound which incorporates a versatile difluoromethyl group on the aniline substitution of a 4-anilinoquinoline kinase inhibitor motif. In addition, the small molecule crystal structure (of the HCL salt) was solved, which uncovered that the difluoromethyl group was disordered within the packing arrangement and also a 126.08(7)° out of plane character between the respective ring systems within the molecule. The compound was fully characterized with 1H/13C-NMR and high-resolution mass spectra (HRMS), with the procedures described.

Published
2020
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4. 1,2,6-thiadiazinones as novel narrow spectrum calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) inhibitors

Author

Asquith, Christopher R. M., Godoi, Paulo H., Couñago, Rafael M., Laitinen, Tuomo, Scott, John W., Langendorf, Christopher G., Oakhill, Jonathan S., Drewry, David H., Zuercher, William J., Koutentis, Panayiotis A., Willson, Timothy M., Kalogirou, Andreas S., Kalogirou, Andreas S. [0000-0002-5476-5805], and Koutentis, Panayiotis A. [0000-0002-4652-7567]

Subjects
0301 basic medicine, Models, Molecular, Pharmaceutical Science, chemistry.chemical_element, thiadiazinone, Calcium-Calmodulin-Dependent Protein Kinase Kinase, Calcium, CaMKK2, Crystallography, X-Ray, 01 natural sciences, kinase inhibitor design, Article, Analytical Chemistry, hinge binder, kinase water network, 03 medical and health sciences, Thiadiazoles, Catalytic Domain, Drug Discovery, Bound water, Humans, Physical and Theoretical Chemistry, Protein kinase A, Protein Kinase Inhibitors, CAMKK2, biology, Molecular Structure, 010405 organic chemistry, Chemistry, Kinase, Organic Chemistry, Active site, Water, 0104 chemical sciences, Molecular Docking Simulation, 030104 developmental biology, Biochemistry, Chemistry (miscellaneous), biology.protein, Molecular Medicine, Function (biology)
Abstract

We demonstrate for the first time that 4H-1,2,6-thiadiazin-4-one (TDZ) can function as a chemotype for the design of ATP-competitive kinase inhibitors. Using insights from a co-crystal structure of a 3,5-bis(arylamino)-4H-1,2,6-thiadiazin-4-one bound to calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), several analogues were identified with micromolar activity through targeted displacement of bound water molecules in the active site. Since the TDZ analogues showed reduced promiscuity compared to their 2,4-dianilinopyrimidine counter parts, they represent starting points for development of highly selective kinase inhibitors. 23 5

Published
2018

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