2. Academic Validation
  3. 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

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

  • J Med Chem. 2020 Jul 23;63(14):7817-7826. doi: 10.1021/acs.jmedchem.0c00596.
Fleur M Ferguson 1,  Yan Liu 2,  Wayne Harshbarger 2,  Ling Huang 3,  Jinhua Wang 1,  Xianming Deng 1,  Stephen J Capuzzi 4,  Eugene N Muratov 4,  Alexander Tropsha 4,  Senthil Muthuswamy 3 5,  Kenneth D Westover 2,  Nathanael S Gray 1
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States.
  • 2 Departments of Radiation Oncology and Biochemistry, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, United States.
  • 3 Cancer Research Institute and Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, United States.
  • 4 UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States.
  • 5 Departments of Medicine and Pathology, Harvard Medical School, Boston, Massachusetts 02215, United States.
PMID: 32530623 DOI: 10.1021/acs.jmedchem.0c00596
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.

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