Discovery of novel small molecule inhibitors of S100P, with in vitro anti-metastatic effects on pancreatic cancer cells

© 2020 The Author(s). This is an open access article published under the terms of the Creative Commons Attribution 4.0 International licence (CC BY 4.0). For further details please see https://creativecommons.org/licenses/by/4.0/.S100P, a calcium- binding protein, is known to advance tumor progression and metastasis in pancreatic and several other cancers. Herein is described the in silico identification of a putative binding pocket of S100P to identify, synthesize and evaluate novel small molecules with the potential to selectively bind S100P and inhibit its activation of cell survival and metastatic pathways. The virtual screening of a drug-like database against the S100P model led to the identification of over 100 clusters of diverse scaffolds. A representative test set identified a number of structurally unrelated hits that inhibit S100P-RAGE interaction, measured by ELISA, and reduce in vitro cell invasion selectively in S100P-expressing pancreatic cancer cells at 10 µM. This study establishes a proof of concept in the potential for rational design of small molecule S100P inhibitors for drug candidate development.Peer reviewe