Design of a small molecule that stimulates vascular endothelial growth factor A enabled by screening RNA fold-small molecule interactions

  • Nat Chem. 2020 Oct;12(10):952-961. doi: 10.1038/s41557-020-0514-4.
Hafeez S Haniff  1 ,  Laurent Knerr  2 ,  Xiaohui Liu  1 ,  Gogce Crynen  3 ,  Jonas Boström  2 ,  Daniel Abegg  1 ,  Alexander Adibekian  1 ,  Elizabeth Lekah  1 ,  Kye Won Wang  4 ,  Michael D Cameron  5 ,  Ilyas Yildirim  4 ,  Malin Lemurell  2 ,  Matthew D Disney  6
Affiliations
  • 1. Department of Chemistry, The Scripps Research Institute, Jupiter, FL, USA.
  • 2. Department of Medicinal Chemistry, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • 3. Informatic Core, The Scripps Research Institute, Jupiter, FL, USA.
  • 4. Department of Chemistry and Biochemistry, Florida Atlantic University, Jupiter, FL, USA.
  • 5. Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, USA.
  • 6. Department of Chemistry, The Scripps Research Institute, Jupiter, FL, USA. [email protected].
PMID: 32839603 DOI: 10.1038/s41557-020-0514-4
Abstract

Vascular endothelial growth factor A (VEGFA) stimulates angiogenesis in human endothelial cells, and increasing its expression is a potential treatment for heart failure. Here, we report the design of a small molecule (TGP-377) that specifically and potently enhances VEGFA expression by the targeting of a non-coding MicroRNA that regulates its expression. A selection-based screen, named two-dimensional combinatorial screening, revealed preferences in small-molecule chemotypes that bind RNA and preferences in the RNA motifs that bind small molecules. The screening program increased the dataset of known RNA motif-small molecule binding partners by 20-fold. Analysis of this dataset against the RNA-mediated pathways that regulate VEGFA defined that the microRNA-377 precursor, which represses Vegfa messenger RNA translation, is druggable in a selective manner. We designed TGP-377 to potently and specifically upregulate VEGFA in human umbilical vein endothelial cells. These studies illustrate the power of two-dimensional combinatorial screening to define molecular recognition events between 'undruggable' biomolecules and small molecules, and the ability of sequence-based design to deliver efficacious structure-specific compounds.

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