@misc{kumar_brunner_schuster_kopp_gries_yan_jurt_moehle_bruns_grotzer_et al._2022, 
  title={Rational discovery of small molecule inhibitor targeting invasion and tumor growth}, 
  DOI={10.21203/rs.3.rs-1359115/v1}, 
  abstractNote={<jats:title>Abstract</jats:title>
        <jats:p>Rational targeting of proteins involved in controlling cancer cell behavior with small bioactive compounds can accelerate anti-cancer drug discovery. We report the identification of a new small molecule compound inhibitor of the FGFR adaptor protein FRS2. Pharmacophore-based computational screening combined with functional, biophysical, and structural binding analyses, led to the identification of low-molecular weight ligands that interact with the PTB domain of FRS2. By assessing the compounds' anti-invasion activity in human FGFR-driven cancer cell models, three chemically distinct bioactive molecules were shortlisted for further analysis. A lead compound was selected that specifically repressed FGFR-driven MAPK activation and matrix invasion and displayed on-target activity in cells. Proteome-wide off-target activity of the primary lead was determined and functional <jats:italic>in vivo</jats:italic> efficacy in an FGFR driven ovarian cancer model confirmed. We propose inhibition of FRS2 by a small molecular PTB domain ligand as a strategy to repress FGF signaling in FGFR-driven human cancers.</jats:p>}, 
  publisher={Research Square Platform LLC}, 
  author={Kumar, Karthiga Santhana and Brunner, Cyrill and Schuster, Matthias and Kopp, Levi and Gries, Alexandre and Yan, Shen and Jurt, Simon and Moehle, Kerstin and Bruns, Dominique and Grotzer, Michael and et al.}, 
  year={2022}, 
  month={Feb}
  }