4-Amino-6-arylamino-pyrimidine-5-carbaldehyde hydrazones as potent ErbB-2/EGFR dual kinase inhibitors

Guozhang Xu; Marta C. Abad; Peter J. Connolly; Michael P. Neeper; Geoffrey T. Struble; Barry A. Springer; Stuart L. Emanuel; Niranjan Pandey; Robert H. Gruninger; Mary Adams; Sandra Moreno-Mazza; Angel R. Fuentes-Pesquera; Steven A. Middleton

doi:10.1016/j.bmcl.2008.07.020

4-Amino-6-arylamino-pyrimidine-5-carbaldehyde hydrazones as potent ErbB-2/EGFR dual kinase inhibitors

Guozhang Xu, Marta C. Abad, Peter J. Connolly, Michael P. Neeper, Geoffrey T. Struble, Barry A. Springer, Stuart L. Emanuel, Niranjan Pandey, Robert H. Gruninger, Mary Adams, Sandra Moreno-Mazza, Angel R. Fuentes-Pesquera, Steven A. Middleton

Research output: Contribution to journal › Article › peer-review

52 Scopus citations

Abstract

Members of a novel class of 4-amino-6-arylamino-pyrimidine-5-carbaldehyde hydrazones were identified as potent dual ErbB-2/EGFR kinase inhibitors using concept-guided design approach. These compounds inhibited the growth of ErbB-2 over-expressing human tumor cell lines (BT474, N87, and SK-BR-3) in vitro. Compound 15 emerged as a key lead and showed significant ability to inhibit growth factor-induced receptor phosphorylation in SK-BR-3 cells (IC₅₀ = 54 nM) and cellular proliferation in vitro (IC₅₀ = 14, 58, and 58 nM for BT474, N87, and SK-BR-3 respectively). The X-ray co-crystal structure of EGFR with a close analog (17) was determined and validated our design rationale.

Original language	English (US)
Pages (from-to)	4615-4619
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	18
Issue number	16
DOIs	https://doi.org/10.1016/j.bmcl.2008.07.020
State	Published - Aug 15 2008
Externally published	Yes

Keywords

Bioisostere
EGFR
ErbB-2
Hydrazones
Quinazoline
Receptor tyrosine kinase

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2008.07.020

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Xu, G., Abad, M. C., Connolly, P. J., Neeper, M. P., Struble, G. T., Springer, B. A., Emanuel, S. L., Pandey, N., Gruninger, R. H., Adams, M., Moreno-Mazza, S., Fuentes-Pesquera, A. R., & Middleton, S. A. (2008). 4-Amino-6-arylamino-pyrimidine-5-carbaldehyde hydrazones as potent ErbB-2/EGFR dual kinase inhibitors. Bioorganic and Medicinal Chemistry Letters, 18(16), 4615-4619. https://doi.org/10.1016/j.bmcl.2008.07.020

Xu, G, Abad, MC, Connolly, PJ, Neeper, MP, Struble, GT, Springer, BA, Emanuel, SL, Pandey, N, Gruninger, RH, Adams, M, Moreno-Mazza, S, Fuentes-Pesquera, AR & Middleton, SA 2008, '4-Amino-6-arylamino-pyrimidine-5-carbaldehyde hydrazones as potent ErbB-2/EGFR dual kinase inhibitors', Bioorganic and Medicinal Chemistry Letters, vol. 18, no. 16, pp. 4615-4619. https://doi.org/10.1016/j.bmcl.2008.07.020

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abstract = "Members of a novel class of 4-amino-6-arylamino-pyrimidine-5-carbaldehyde hydrazones were identified as potent dual ErbB-2/EGFR kinase inhibitors using concept-guided design approach. These compounds inhibited the growth of ErbB-2 over-expressing human tumor cell lines (BT474, N87, and SK-BR-3) in vitro. Compound 15 emerged as a key lead and showed significant ability to inhibit growth factor-induced receptor phosphorylation in SK-BR-3 cells (IC50 = 54 nM) and cellular proliferation in vitro (IC50 = 14, 58, and 58 nM for BT474, N87, and SK-BR-3 respectively). The X-ray co-crystal structure of EGFR with a close analog (17) was determined and validated our design rationale.",

keywords = "Bioisostere, EGFR, ErbB-2, Hydrazones, Quinazoline, Receptor tyrosine kinase",

author = "Guozhang Xu and Abad, {Marta C.} and Connolly, {Peter J.} and Neeper, {Michael P.} and Struble, {Geoffrey T.} and Springer, {Barry A.} and Emanuel, {Stuart L.} and Niranjan Pandey and Gruninger, {Robert H.} and Mary Adams and Sandra Moreno-Mazza and Fuentes-Pesquera, {Angel R.} and Middleton, {Steven A.}",

note = "Funding Information: Use of the IMCA-CAT beamline 17-ID (or 17-BM) at the Advanced Photon Source was supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with the Center for Advanced Radiation Sources at the University of Chicago. ",

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doi = "10.1016/j.bmcl.2008.07.020",

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AU - Connolly, Peter J.

AU - Neeper, Michael P.

AU - Struble, Geoffrey T.

AU - Springer, Barry A.

AU - Emanuel, Stuart L.

AU - Pandey, Niranjan

AU - Gruninger, Robert H.

AU - Adams, Mary

AU - Moreno-Mazza, Sandra

AU - Fuentes-Pesquera, Angel R.

AU - Middleton, Steven A.

N1 - Funding Information: Use of the IMCA-CAT beamline 17-ID (or 17-BM) at the Advanced Photon Source was supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with the Center for Advanced Radiation Sources at the University of Chicago.

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N2 - Members of a novel class of 4-amino-6-arylamino-pyrimidine-5-carbaldehyde hydrazones were identified as potent dual ErbB-2/EGFR kinase inhibitors using concept-guided design approach. These compounds inhibited the growth of ErbB-2 over-expressing human tumor cell lines (BT474, N87, and SK-BR-3) in vitro. Compound 15 emerged as a key lead and showed significant ability to inhibit growth factor-induced receptor phosphorylation in SK-BR-3 cells (IC50 = 54 nM) and cellular proliferation in vitro (IC50 = 14, 58, and 58 nM for BT474, N87, and SK-BR-3 respectively). The X-ray co-crystal structure of EGFR with a close analog (17) was determined and validated our design rationale.

AB - Members of a novel class of 4-amino-6-arylamino-pyrimidine-5-carbaldehyde hydrazones were identified as potent dual ErbB-2/EGFR kinase inhibitors using concept-guided design approach. These compounds inhibited the growth of ErbB-2 over-expressing human tumor cell lines (BT474, N87, and SK-BR-3) in vitro. Compound 15 emerged as a key lead and showed significant ability to inhibit growth factor-induced receptor phosphorylation in SK-BR-3 cells (IC50 = 54 nM) and cellular proliferation in vitro (IC50 = 14, 58, and 58 nM for BT474, N87, and SK-BR-3 respectively). The X-ray co-crystal structure of EGFR with a close analog (17) was determined and validated our design rationale.

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4-Amino-6-arylamino-pyrimidine-5-carbaldehyde hydrazones as potent ErbB-2/EGFR dual kinase inhibitors

Abstract

Keywords

ASJC Scopus subject areas

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