1. Academic Validation
  2. Identification of DK419, a potent inhibitor of Wnt/β-catenin signaling and colorectal cancer growth

Identification of DK419, a potent inhibitor of Wnt/β-catenin signaling and colorectal cancer growth

  • Bioorg Med Chem. 2018 Nov 1;26(20):5435-5442. doi: 10.1016/j.bmc.2018.09.016.
Jiangbo Wang 1 Robert A Mook Jr 2 Xiu-Rong Ren 2 Qingfu Zhang 3 Genevieve Jing 2 Min Lu 2 Ivan Spasojevic 4 H Kim Lyerly 5 David Hsu 2 Wei Chen 6
Affiliations

Affiliations

  • 1 Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States. Electronic address: jiangbo.wang@duke.edu.
  • 2 Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States.
  • 3 Department of Pathology, Duke University Medical Center, Durham, NC 27710, United States; Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shengyang 110001, China.
  • 4 Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States; Duke Cancer Institute, PK/PD Core Laboratory, Durham, NC 27710, United States.
  • 5 Department of Surgery, Duke University Medical Center, Durham, NC 27710, United States.
  • 6 Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States. Electronic address: w.chen@duke.edu.
Abstract

The Wnt signaling pathway is critical for normal tissue development and is an underlying mechanism of disease when dysregulated. Previously, we reported that the drug Niclosamide inhibits Wnt/β-catenin signaling by decreasing the cytosolic levels of Dishevelled and β-catenin, and inhibits the growth of colon cancers both in vitro and in vivo. Since the discovery of Niclosamide's anthelmintic activity, a growing body of literature indicates that Niclosamide is a multifunctional drug. In an effort to identify derivatives of Niclosamide with improved pharmacokinetic properties that maintain the multifunctional drug activity of Niclosamide for clinical evaluation, we designed DK419, a derivative containing a 1H-benzo[d]imidazole-4-carboxamide substructure, using the structure-activity relationships (SAR) of the Niclosamide salicylanilide chemotype. Similar to Niclosamide, we found DK419 inhibited Wnt/β-catenin signaling, altered cellular oxygen consumption rate and induced production of pAMPK. Moreover, we found DK419 inhibited the growth of CRC tumor cells in vitro, had good plasma exposure when dosed orally, and inhibited the growth of patient derived CRC240 tumor explants in mice dosed orally. DK419, a derivative of Niclosamide with multifunctional activity and improved pharmacokinetic properties, is a promising agent to treat colorectal Cancer, Wnt-related diseases and Other Diseases in which Niclosamide has demonstrated functional activity.

Keywords

Cancer; Drug design; Niclosamide; Oxidative phosphorylation; Small molecule; Wnt signaling inhibitor.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-112799
    99.88%, Wnt/β-catenin Inhibitor