2. Academic Validation
  3. Characterization of Small Molecules Inhibiting the Pro-Angiogenic Activity of the Zinc Finger Transcription Factor Vezf1

Characterization of Small Molecules Inhibiting the Pro-Angiogenic Activity of the Zinc Finger Transcription Factor Vezf1

  • Molecules. 2018 Jul 3;23(7):1615. doi: 10.3390/molecules23071615.
Ming He 1,  Qianyi Yang 2 3,  Allison B Norvil 4,  David Sherris 5,  Humaira Gowher 6 7
Affiliations

Affiliations

  • 1 Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA. he261@purdue.edu.
  • 2 Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA. qianyiyang@wustl.edu.
  • 3 Department of Anesthesiology, Washington University School of Medicine, 660 S Euclid Ave, St. Louis, MO 63110, USA. qianyiyang@wustl.edu.
  • 4 Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA. anorvil@purdue.edu.
  • 5 GenAdam Therapeutics, Inc., 37 Neillian Crescent, Jamaica Plain, MA 02130, USA. dsherris@genadamthera.com.
  • 6 Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA. hgowher@purdue.edu.
  • 7 Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA. hgowher@purdue.edu.
PMID: 29970794 DOI: 10.3390/molecules23071615
Abstract

Discovery of inhibitors for endothelial-related transcription factors can contribute to the development of anti-angiogenic therapies that treat various diseases, including Cancer. The role of transcription factor Vezf1 in vascular development and regulation of angiogenesis has been defined by several earlier studies. Through construction of a computational model for Vezf1, work here has identified a novel small molecule drug capable of inhibiting Vezf1 from binding to its cognate DNA binding site. Using structure-based design and virtual screening of the NCI Diversity Compound Library, 12 shortlisted compounds were tested for their ability to interfere with the binding of Vezf1 to DNA using electrophoretic gel mobility shift assays. We identified one compound, T4, which has an IC50 of 20 μM. Using murine endothelial cells, MSS31, we tested the effect of T4 on endothelial cell viability and angiogenesis by using tube formation assay. Our data show that addition of T4 in Cell Culture medium does not affect cell viability at concentrations lower or equal to its IC 50 but strongly inhibits the network formation by MSS31 in the tube formation assays. Given its potential efficacy, this inhibitor has significant therapeutic potential in several human diseases.

Keywords

MSS31; Vezf1; angiogenesis; endothelial cells; small molecule inhibitors computational modeling; tube formation; vascular biology.

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