Synthesis and Structure-Activity Relationships of DCLK1 Kinase Inhibitors Based on a 5,11-Dihydro-6 H-benzo[ e]pyrimido[5,4- b][1,4]diazepin-6-one Scaffold

Fleur M. Ferguson; Yan Liu; Wayne Harshbarger; Ling Huang; Jinhua Wang; Xianming Deng; Stephen J. Capuzzi; Eugene N. Muratov; Alexander Tropsha; Senthil Muthuswamy; Kenneth D. Westover; Nathanael S. Gray

doi:10.1021/acs.jmedchem.0c00596

Synthesis and Structure-Activity Relationships of DCLK1 Kinase Inhibitors Based on a 5,11-Dihydro-6 H-benzo[ e]pyrimido[5,4- b][1,4]diazepin-6-one Scaffold

Fleur M. Ferguson, Yan Liu, Wayne Harshbarger, Ling Huang, Jinhua Wang, Xianming Deng, Stephen J. Capuzzi, Eugene N. Muratov, Alexander Tropsha, Senthil Muthuswamy, Kenneth D. Westover, Nathanael S. Gray

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

18 Scopus citations

Abstract

Doublecortin-like kinase 1 (DCLK1) is a serine/threonine kinase that is overexpressed in gastrointestinal cancers, including esophageal, gastric, colorectal, and pancreatic cancers. DCLK1 is also used as a marker of tuft cells, which regulate type II immunity in the gut. However, the substrates and functions of DCLK1 are understudied. We recently described the first selective DCLK1/2 inhibitor, DCLK1-IN-1, developed to aid the functional characterization of this important kinase. Here we describe the synthesis and structure-activity relationships of 5,11-dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-one DCLK1 inhibitors, resulting in the identification of DCLK1-IN-1.

Original language	English (US)
Pages (from-to)	7817-7826
Number of pages	10
Journal	Journal of Medicinal Chemistry
Volume	63
Issue number	14
DOIs	https://doi.org/10.1021/acs.jmedchem.0c00596
State	Published - Jul 23 2020
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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Ferguson, F. M., Liu, Y., Harshbarger, W., Huang, L., Wang, J., Deng, X., Capuzzi, S. J., Muratov, E. N., Tropsha, A., Muthuswamy, S., Westover, K. D., & Gray, N. S. (2020). Synthesis and Structure-Activity Relationships of DCLK1 Kinase Inhibitors Based on a 5,11-Dihydro-6 H-benzo[ e]pyrimido[5,4- b][1,4]diazepin-6-one Scaffold. Journal of Medicinal Chemistry, 63(14), 7817-7826. https://doi.org/10.1021/acs.jmedchem.0c00596

Ferguson, FM, Liu, Y, Harshbarger, W, Huang, L, Wang, J, Deng, X, Capuzzi, SJ, Muratov, EN, Tropsha, A, Muthuswamy, S, Westover, KD & Gray, NS 2020, 'Synthesis and Structure-Activity Relationships of DCLK1 Kinase Inhibitors Based on a 5,11-Dihydro-6 H-benzo[ e]pyrimido[5,4- b][1,4]diazepin-6-one Scaffold', Journal of Medicinal Chemistry, vol. 63, no. 14, pp. 7817-7826. https://doi.org/10.1021/acs.jmedchem.0c00596

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title = "Synthesis and Structure-Activity Relationships of DCLK1 Kinase Inhibitors Based on a 5,11-Dihydro-6 H-benzo[ e]pyrimido[5,4- b][1,4]diazepin-6-one Scaffold",

abstract = "Doublecortin-like kinase 1 (DCLK1) is a serine/threonine kinase that is overexpressed in gastrointestinal cancers, including esophageal, gastric, colorectal, and pancreatic cancers. DCLK1 is also used as a marker of tuft cells, which regulate type II immunity in the gut. However, the substrates and functions of DCLK1 are understudied. We recently described the first selective DCLK1/2 inhibitor, DCLK1-IN-1, developed to aid the functional characterization of this important kinase. Here we describe the synthesis and structure-activity relationships of 5,11-dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-one DCLK1 inhibitors, resulting in the identification of DCLK1-IN-1.",

author = "Ferguson, {Fleur M.} and Yan Liu and Wayne Harshbarger and Ling Huang and Jinhua Wang and Xianming Deng and Capuzzi, {Stephen J.} and Muratov, {Eugene N.} and Alexander Tropsha and Senthil Muthuswamy and Westover, {Kenneth D.} and Gray, {Nathanael S.}",

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AU - Ferguson, Fleur M.

AU - Liu, Yan

AU - Harshbarger, Wayne

AU - Huang, Ling

AU - Wang, Jinhua

AU - Deng, Xianming

AU - Capuzzi, Stephen J.

AU - Muratov, Eugene N.

AU - Tropsha, Alexander

AU - Muthuswamy, Senthil

AU - Westover, Kenneth D.

AU - Gray, Nathanael S.

PY - 2020/7/23

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N2 - Doublecortin-like kinase 1 (DCLK1) is a serine/threonine kinase that is overexpressed in gastrointestinal cancers, including esophageal, gastric, colorectal, and pancreatic cancers. DCLK1 is also used as a marker of tuft cells, which regulate type II immunity in the gut. However, the substrates and functions of DCLK1 are understudied. We recently described the first selective DCLK1/2 inhibitor, DCLK1-IN-1, developed to aid the functional characterization of this important kinase. Here we describe the synthesis and structure-activity relationships of 5,11-dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-one DCLK1 inhibitors, resulting in the identification of DCLK1-IN-1.

AB - Doublecortin-like kinase 1 (DCLK1) is a serine/threonine kinase that is overexpressed in gastrointestinal cancers, including esophageal, gastric, colorectal, and pancreatic cancers. DCLK1 is also used as a marker of tuft cells, which regulate type II immunity in the gut. However, the substrates and functions of DCLK1 are understudied. We recently described the first selective DCLK1/2 inhibitor, DCLK1-IN-1, developed to aid the functional characterization of this important kinase. Here we describe the synthesis and structure-activity relationships of 5,11-dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-one DCLK1 inhibitors, resulting in the identification of DCLK1-IN-1.

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Synthesis and Structure-Activity Relationships of DCLK1 Kinase Inhibitors Based on a 5,11-Dihydro-6 H-benzo[ e]pyrimido[5,4- b][1,4]diazepin-6-one Scaffold

Abstract

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