1. Academic Validation
  2. Improving the solubility and antileukemia activity of Wnt/β-catenin signaling inhibitors by disrupting molecular planarity

Improving the solubility and antileukemia activity of Wnt/β-catenin signaling inhibitors by disrupting molecular planarity

  • Bioorg Med Chem. 2022 Sep 1:69:116890. doi: 10.1016/j.bmc.2022.116890.
Yong Ai 1 Srilatha Sakamuru 2 Greg Imler 3 Menghang Xia 2 Fengtian Xue 4
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, United States.
  • 2 9800 Medical Center Drive, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, United States.
  • 3 Naval Research Laboratory, Code 6930, 4555 Overlook Avenue, Washington, D.C. 20375, United States.
  • 4 Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, United States. Electronic address: fxue@rx.umaryland.edu.
Abstract

Leukemia cells depend on the Wnt/β-catenin signaling pathway for their growth. Pyrvinium, a known Wnt signaling inhibitor, has demonstrated promising efficacy in the treatment of the aggressive blast phase chronic myeloid leukemia (BP-CML). We previously developed potent inhibitors 1-2 for the Wnt/β-catenin signaling pathway. However, the further application of these compounds as anti-leukemia agents is limited by their modest anti-leukemia activity in cells and poor aqueous solubility, due to the high molecular planarity of the chemical scaffold. Here, we reported our efforts in the synthesis and in vitro evaluation of 18 new compounds (4a-r) that have been designed to disrupt the molecular planarity of the chemical scaffold. Several compounds of the series showed significantly improved anti-leukemia activity and aqueous solubility. As a highlight, compounds 4c not only maintained excellent inhibitory potency (IC50 = 1.3 nM) for Wnt signaling but also demonstrated good anti-leukemia potency (IC50 = 0.9 µM) in the CML K562 cells. Moreover, compound 4c had an aqueous solubility of 5.9 µg/mL, which is over 50-fold enhanced compared to its parents 1-2.

Keywords

Chronic myeloid leukemia way; Molecular planarity; Small molecule inhibitors; Wnt/β-catenin signaling pathway.

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