New insights into 4-anilinoquinazolines as inhibitors of cardiac troponin I-interacting kinase (TNNI3K)
New insights into 4-anilinoquinazolines as inhibitors of cardiac troponin I-interacting kinase (TNNI3K)
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.
4-anilino-quinazolines, Cardiac troponin I-interacting kinase (TNNi3K), Conformational flexibility, Hinge binder, Kinase inhibitor design
Asquith, Christopher R.M.
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Laitinen, Tuomo
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Wells, Carrow I.
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Tizzard, Graham J.
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Zuercher, William J.
e464feb0-ea00-4c90-8fb4-2f31caba1040
7 April 2020
Asquith, Christopher R.M.
51f24044-1f40-43c7-806a-2e78fdcc2733
Laitinen, Tuomo
b37037c5-4eac-4533-8246-5a49213bae9b
Wells, Carrow I.
b1b55315-9748-46cb-919f-663298061454
Tizzard, Graham J.
8474c0fa-40df-43a6-a662-7f3c4722dbf2
Zuercher, William J.
e464feb0-ea00-4c90-8fb4-2f31caba1040
Asquith, Christopher R.M., Laitinen, Tuomo, Wells, Carrow I., Tizzard, Graham J. and Zuercher, William J.
(2020)
New insights into 4-anilinoquinazolines as inhibitors of cardiac troponin I-interacting kinase (TNNI3K).
Molecules, 25 (7), [25071697].
(doi:10.3390/molecules25071697).
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.
Text
New Insights into 4-Anilinoquinazolines
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Accepted/In Press date: 3 April 2020
e-pub ahead of print date: 7 April 2020
Published date: 7 April 2020
Keywords:
4-anilino-quinazolines, Cardiac troponin I-interacting kinase (TNNi3K), Conformational flexibility, Hinge binder, Kinase inhibitor design
Identifiers
Local EPrints ID: 440884
URI: http://eprints.soton.ac.uk/id/eprint/440884
ISSN: 1420-3049
PURE UUID: 88ceee14-e361-4c35-83bd-5161ab6debf9
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Date deposited: 21 May 2020 16:30
Last modified: 18 Mar 2024 02:54
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Contributors
Author:
Christopher R.M. Asquith
Author:
Tuomo Laitinen
Author:
Carrow I. Wells
Author:
William J. Zuercher
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