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Targeting an EGFR water network with 4-anilinoquin(az)oline inhibitors for chordoma

Targeting an EGFR water network with 4-anilinoquin(az)oline inhibitors for chordoma
Targeting an EGFR water network with 4-anilinoquin(az)oline inhibitors for chordoma

Quinoline- and quinazoline-based kinase inhibitors of the epidermal growth factor receptor (EGFR) have been used to target non-small cell lung cancer (NSCLC) and chordomas with varying amounts of success. We designed and prepared compounds to probe several key structural features including an interaction with Asp855 within the EGFR DGF motif and interactions with the active site water network. EGFR target engagement was then evaluated in a cellular assay, with the inhibitors then profiled in representative cellular models of NSCLC and chordomas. In addition, structure–activity relationship insight into EGFR inhibitor design with potent dimethoxyquin(az)olines identified compounds 1 [N-(3-ethynylphenyl)-6,7-dimethoxyquinolin-4-amine], 4 [N-(3-ethynylphenyl)-6,7-dimethoxyquinazolin-4-amine], and 7 [4-((3-ethynylphenyl)amino)-6,7-dimethoxyquinoline-3-carbonitrile]. We also identified 6,7-dimethoxy-N-(4-((4-methylbenzyl)oxy)phenyl)quinolin-4-amine (compound 18), which is the most potent inhibitor (IC50=310 nm) of the UCH-2 chordoma cell line to date.

4-anilinoquinazolines, 4-anilinoquinolines, chordoma, epidermal growth factor receptor (EGFR), non-small cell lung cancer (NSCLC)
1860-7179
1693-1700
Asquith, Christopher R.M.
51f24044-1f40-43c7-806a-2e78fdcc2733
Maffuid, Kaitlyn A.
b7fa0436-2f89-4d35-85b4-72542478ee3e
Laitinen, Tuomo
b37037c5-4eac-4533-8246-5a49213bae9b
Torrice, Chad D.
5ba5d52d-67b4-45bf-a33a-10b6a6d08f88
Tizzard, Graham J.
8474c0fa-40df-43a6-a662-7f3c4722dbf2
Crona, Daniel J.
44fdc91b-77f6-4532-975c-118be3c9ec5e
Zuercher, William J.
e464feb0-ea00-4c90-8fb4-2f31caba1040
Asquith, Christopher R.M.
51f24044-1f40-43c7-806a-2e78fdcc2733
Maffuid, Kaitlyn A.
b7fa0436-2f89-4d35-85b4-72542478ee3e
Laitinen, Tuomo
b37037c5-4eac-4533-8246-5a49213bae9b
Torrice, Chad D.
5ba5d52d-67b4-45bf-a33a-10b6a6d08f88
Tizzard, Graham J.
8474c0fa-40df-43a6-a662-7f3c4722dbf2
Crona, Daniel J.
44fdc91b-77f6-4532-975c-118be3c9ec5e
Zuercher, William J.
e464feb0-ea00-4c90-8fb4-2f31caba1040

Asquith, Christopher R.M., Maffuid, Kaitlyn A., Laitinen, Tuomo, Torrice, Chad D., Tizzard, Graham J., Crona, Daniel J. and Zuercher, William J. (2019) Targeting an EGFR water network with 4-anilinoquin(az)oline inhibitors for chordoma. ChemMedChem, 14 (19), 1693-1700. (doi:10.1002/cmdc.201900428).

Record type: Article

Abstract

Quinoline- and quinazoline-based kinase inhibitors of the epidermal growth factor receptor (EGFR) have been used to target non-small cell lung cancer (NSCLC) and chordomas with varying amounts of success. We designed and prepared compounds to probe several key structural features including an interaction with Asp855 within the EGFR DGF motif and interactions with the active site water network. EGFR target engagement was then evaluated in a cellular assay, with the inhibitors then profiled in representative cellular models of NSCLC and chordomas. In addition, structure–activity relationship insight into EGFR inhibitor design with potent dimethoxyquin(az)olines identified compounds 1 [N-(3-ethynylphenyl)-6,7-dimethoxyquinolin-4-amine], 4 [N-(3-ethynylphenyl)-6,7-dimethoxyquinazolin-4-amine], and 7 [4-((3-ethynylphenyl)amino)-6,7-dimethoxyquinoline-3-carbonitrile]. We also identified 6,7-dimethoxy-N-(4-((4-methylbenzyl)oxy)phenyl)quinolin-4-amine (compound 18), which is the most potent inhibitor (IC50=310 nm) of the UCH-2 chordoma cell line to date.

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CMC EGFR 4thAug2019 - Accepted Manuscript
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Accepted/In Press date: 5 August 2019
e-pub ahead of print date: 19 August 2019
Published date: 4 October 2019
Keywords: 4-anilinoquinazolines, 4-anilinoquinolines, chordoma, epidermal growth factor receptor (EGFR), non-small cell lung cancer (NSCLC)

Identifiers

Local EPrints ID: 435533
URI: http://eprints.soton.ac.uk/id/eprint/435533
ISSN: 1860-7179
PURE UUID: d5c68a81-c8d8-4ad8-96a0-a3a3b6d79e01
ORCID for Graham J. Tizzard: ORCID iD orcid.org/0000-0002-1577-5779

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Date deposited: 08 Nov 2019 17:30
Last modified: 15 Sep 2021 04:39

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