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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)
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
1420-3049
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.
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).

Record type: Article

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.

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New Insights into 4-Anilinoquinazolines - Version of Record
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Accepted/In Press date: 3 April 2020
e-pub ahead of print 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
ORCID for Graham J. Tizzard: ORCID iD orcid.org/0000-0002-1577-5779

Catalogue record

Date deposited: 21 May 2020 16:30
Last modified: 26 Nov 2021 02:45

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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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