Discovery of a 2,4-diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysine methyltransferase G9a

Feng Liu; Xin Chen; Abdellah Allali-Hassani; Amy M. Quinn; Gregory A. Wasney; Aiping Dong; Dalia Barsyte; Ivona Kozieradzki; Guillermo Senisterra; Irene Chau; Alena Siarheyeva; Dmitri B. Kireev; Ajit Jadhav; J. Martin Herold; Stephen V. Frye; Cheryl H. Arrowsmith; Peter J. Brown; Anton Simeonov; Masoud Vedadi; Jian Jin

doi:10.1021/jm901543m

Discovery of a 2,4-diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysine methyltransferase G9a

Feng Liu
, Xin Chen
, Abdellah Allali-Hassani
, Amy M. Quinn
, Gregory A. Wasney
, Aiping Dong
, Dalia Barsyte
, Ivona Kozieradzki
, Guillermo Senisterra
, Irene Chau
, Alena Siarheyeva
, Dmitri B. Kireev
, Ajit Jadhav
, J. Martin Herold
, Stephen V. Frye
, Cheryl H. Arrowsmith
, Peter J. Brown
, Anton Simeonov
, Masoud Vedadi
, Jian Jin

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

227 Scopus citations

Abstract

SAR exploration of the 2,4-diamino-6,7-dimethoxyquinazoline template led to the discovery of 8 (UNC0224) as a potent and selective G9a inhibitor. A high resolution X-ray crystal structure of the G9a-8 complex, the first cocrystal structure of G9a with a small molecule inhibitor, was obtained. The cocrystal structure validated our binding hypothesis and will enable structure-based design of novel inhibitors. 8 is a useful tool for investigating the biology of G9a and its roles in chromatin remodeling.

Original language	English
Pages (from-to)	7950-7953
Number of pages	4
Journal	Journal of Medicinal Chemistry
Volume	52
Issue number	24
DOIs	https://doi.org/10.1021/jm901543m
State	Published - 24 Dec 2009
Externally published	Yes

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Liu, F., Chen, X., Allali-Hassani, A., Quinn, A. M., Wasney, G. A., Dong, A., Barsyte, D., Kozieradzki, I., Senisterra, G., Chau, I., Siarheyeva, A., Kireev, D. B., Jadhav, A., Herold, J. M., Frye, S. V., Arrowsmith, C. H., Brown, P. J., Simeonov, A., Vedadi, M., & Jin, J. (2009). Discovery of a 2,4-diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysine methyltransferase G9a. Journal of Medicinal Chemistry, 52(24), 7950-7953. https://doi.org/10.1021/jm901543m

@article{667221fb71da4d6f9a0bd055944e3934,

title = "Discovery of a 2,4-diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysine methyltransferase G9a",

abstract = "SAR exploration of the 2,4-diamino-6,7-dimethoxyquinazoline template led to the discovery of 8 (UNC0224) as a potent and selective G9a inhibitor. A high resolution X-ray crystal structure of the G9a-8 complex, the first cocrystal structure of G9a with a small molecule inhibitor, was obtained. The cocrystal structure validated our binding hypothesis and will enable structure-based design of novel inhibitors. 8 is a useful tool for investigating the biology of G9a and its roles in chromatin remodeling.",

author = "Feng Liu and Xin Chen and Abdellah Allali-Hassani and Quinn, \{Amy M.\} and Wasney, \{Gregory A.\} and Aiping Dong and Dalia Barsyte and Ivona Kozieradzki and Guillermo Senisterra and Irene Chau and Alena Siarheyeva and Kireev, \{Dmitri B.\} and Ajit Jadhav and Herold, \{J. Martin\} and Frye, \{Stephen V.\} and Arrowsmith, \{Cheryl H.\} and Brown, \{Peter J.\} and Anton Simeonov and Masoud Vedadi and Jian Jin",

year = "2009",

month = dec,

day = "24",

doi = "10.1021/jm901543m",

language = "English",

volume = "52",

pages = "7950--7953",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "24",

}

Liu, F, Chen, X, Allali-Hassani, A, Quinn, AM, Wasney, GA, Dong, A, Barsyte, D, Kozieradzki, I, Senisterra, G, Chau, I, Siarheyeva, A, Kireev, DB, Jadhav, A, Herold, JM, Frye, SV, Arrowsmith, CH, Brown, PJ, Simeonov, A, Vedadi, M & Jin, J 2009, 'Discovery of a 2,4-diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysine methyltransferase G9a', Journal of Medicinal Chemistry, vol. 52, no. 24, pp. 7950-7953. https://doi.org/10.1021/jm901543m

TY - JOUR

T1 - Discovery of a 2,4-diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysine methyltransferase G9a

AU - Liu, Feng

AU - Chen, Xin

AU - Allali-Hassani, Abdellah

AU - Quinn, Amy M.

AU - Wasney, Gregory A.

AU - Dong, Aiping

AU - Barsyte, Dalia

AU - Kozieradzki, Ivona

AU - Senisterra, Guillermo

AU - Chau, Irene

AU - Siarheyeva, Alena

AU - Kireev, Dmitri B.

AU - Jadhav, Ajit

AU - Herold, J. Martin

AU - Frye, Stephen V.

AU - Arrowsmith, Cheryl H.

AU - Brown, Peter J.

AU - Simeonov, Anton

AU - Vedadi, Masoud

AU - Jin, Jian

PY - 2009/12/24

Y1 - 2009/12/24

N2 - SAR exploration of the 2,4-diamino-6,7-dimethoxyquinazoline template led to the discovery of 8 (UNC0224) as a potent and selective G9a inhibitor. A high resolution X-ray crystal structure of the G9a-8 complex, the first cocrystal structure of G9a with a small molecule inhibitor, was obtained. The cocrystal structure validated our binding hypothesis and will enable structure-based design of novel inhibitors. 8 is a useful tool for investigating the biology of G9a and its roles in chromatin remodeling.

AB - SAR exploration of the 2,4-diamino-6,7-dimethoxyquinazoline template led to the discovery of 8 (UNC0224) as a potent and selective G9a inhibitor. A high resolution X-ray crystal structure of the G9a-8 complex, the first cocrystal structure of G9a with a small molecule inhibitor, was obtained. The cocrystal structure validated our binding hypothesis and will enable structure-based design of novel inhibitors. 8 is a useful tool for investigating the biology of G9a and its roles in chromatin remodeling.

UR - https://www.scopus.com/pages/publications/73249124141

U2 - 10.1021/jm901543m

DO - 10.1021/jm901543m

M3 - Article

C2 - 19891491

AN - SCOPUS:73249124141

SN - 0022-2623

VL - 52

SP - 7950

EP - 7953

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 24

ER -

Discovery of a 2,4-diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysine methyltransferase G9a

Abstract

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