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 journalArticle

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 languageEnglish (US)
Pages (from-to)7817-7826
Number of pages10
JournalJournal of Medicinal Chemistry
Volume63
Issue number14
DOIs
StatePublished - Jul 23 2020

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