2. Academic Validation
  3. Exploration of naphthoquinone analogs in targeting the TCF-DNA interaction to inhibit the Wnt/β-catenin signaling pathway

Exploration of naphthoquinone analogs in targeting the TCF-DNA interaction to inhibit the Wnt/β-catenin signaling pathway

  • Bioorg Chem. 2022 Jul;124:105812. doi: 10.1016/j.bioorg.2022.105812.
Andrew Morris 1,  Rosalie Hoyle 2,  Piyusha P Pagare 1,  Shadid Uz Zaman 2,  Zhikun Ma 2,  Jiong Li 3,  Yan Zhang 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, United States.
  • 2 Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, United States; The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, United States.
  • 3 Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, United States; The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, United States; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298-0540, United States; Department of Oral and Craniofacial Molecular Biology, School of Dentistry, Virginia Commonwealth University, Richmond, VA 23298-0540, United States; Philips Institute for Oral Health Research, School of Dentistry, Virginia Commonwealth University, Richmond, VA 23298-0540, United States. Electronic address: jli29@vcu.edu.
  • 4 Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, United States; The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, United States; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298-0540, United States. Electronic address: yzhang2@vcu.edu.
PMID: 35447408 DOI: 10.1016/j.bioorg.2022.105812
Abstract

The Wnt/β-catenin signaling pathway plays extensive roles in Cancer initiation, proliferation, and development, and has been implicated in the regulation of stem cells in the intestinal crypt, widely accepted as responsible for colorectal Cancer (CRC) origination. This pathway has been a target of interest for many years for chemotherapeutic development of CRC due to its implication in most cases. Previously, a series of naphthoquinone analogs have been identified to inhibit the Wnt/β-catenin. It was postulated that these compounds exhibit their inhibitory activity via binding to β-catenin at the β-catenin/TCF4 interaction interface. In this study, we aimed to further define the critical pharmacophore for these compounds and verify their mechanisms of action for their abilities to inhibit the Wnt/β-catenin signaling pathway. Interestingly, our data suggested two of the compounds, compounds 3 and 6, may potently inhibit the Wnt/β-catenin signaling pathway via inhibition of the TCF4/DNA interaction, a novel finding compared to previous studies on these compounds. Our computational studies suggested that the compounds bound within the DNA binding HMG-box domain of TCF4 to elicit their inhibitory action. These compounds inhibited Wnt signaling in a dose dependent manner, suppressed Wnt direct target genes and demonstrated unforeseen degradation of the TCF4 protein. Thus, this study revealed a potentially novel mechanism of action of the chloro-naphthoquinone as possibly a multi-targeting scaffold, which warrants further investigation in future drug discovery on the 'undruggable" TCF proteins and an aberrantly activated Wnt/β-catenin signaling pathway.

Keywords

Cancer stem cell; Colorectal cancer; Naphthoquinone; Transcription; Wnt target genes; Wnt-signaling.

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