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

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 sele...

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Autores principales: Camara, Ramatoulie, Ogbeni, Deborah, Gerstmann, Lisa, Ostovar, Mehrnoosh, Hurer, Ellie, Scott, Mark, Mahmoud, Nasir G., Radon, Tomasz, Crnogorac-Jurcevic, Tatjana, Patel, Pryank, Mackenzie, Louise S., Chau, David Y.S., Kirton, Stewart B., Rossiter, Sharon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Editions Scientifiques Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501730/
https://www.ncbi.nlm.nih.gov/pubmed/32707527
http://dx.doi.org/10.1016/j.ejmech.2020.112621
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author Camara, Ramatoulie
Ogbeni, Deborah
Gerstmann, Lisa
Ostovar, Mehrnoosh
Hurer, Ellie
Scott, Mark
Mahmoud, Nasir G.
Radon, Tomasz
Crnogorac-Jurcevic, Tatjana
Patel, Pryank
Mackenzie, Louise S.
Chau, David Y.S.
Kirton, Stewart B.
Rossiter, Sharon
author_facet Camara, Ramatoulie
Ogbeni, Deborah
Gerstmann, Lisa
Ostovar, Mehrnoosh
Hurer, Ellie
Scott, Mark
Mahmoud, Nasir G.
Radon, Tomasz
Crnogorac-Jurcevic, Tatjana
Patel, Pryank
Mackenzie, Louise S.
Chau, David Y.S.
Kirton, Stewart B.
Rossiter, Sharon
author_sort Camara, Ramatoulie
collection PubMed
description 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.
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spelling pubmed-75017302020-10-01 Discovery of novel small molecule inhibitors of S100P with in vitro anti-metastatic effects on pancreatic cancer cells Camara, Ramatoulie Ogbeni, Deborah Gerstmann, Lisa Ostovar, Mehrnoosh Hurer, Ellie Scott, Mark Mahmoud, Nasir G. Radon, Tomasz Crnogorac-Jurcevic, Tatjana Patel, Pryank Mackenzie, Louise S. Chau, David Y.S. Kirton, Stewart B. Rossiter, Sharon Eur J Med Chem Research Paper 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. Editions Scientifiques Elsevier 2020-10-01 /pmc/articles/PMC7501730/ /pubmed/32707527 http://dx.doi.org/10.1016/j.ejmech.2020.112621 Text en © 2020 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Paper
Camara, Ramatoulie
Ogbeni, Deborah
Gerstmann, Lisa
Ostovar, Mehrnoosh
Hurer, Ellie
Scott, Mark
Mahmoud, Nasir G.
Radon, Tomasz
Crnogorac-Jurcevic, Tatjana
Patel, Pryank
Mackenzie, Louise S.
Chau, David Y.S.
Kirton, Stewart B.
Rossiter, Sharon
Discovery of novel small molecule inhibitors of S100P with in vitro anti-metastatic effects on pancreatic cancer cells
title Discovery of novel small molecule inhibitors of S100P with in vitro anti-metastatic effects on pancreatic cancer cells
title_full Discovery of novel small molecule inhibitors of S100P with in vitro anti-metastatic effects on pancreatic cancer cells
title_fullStr Discovery of novel small molecule inhibitors of S100P with in vitro anti-metastatic effects on pancreatic cancer cells
title_full_unstemmed Discovery of novel small molecule inhibitors of S100P with in vitro anti-metastatic effects on pancreatic cancer cells
title_short Discovery of novel small molecule inhibitors of S100P with in vitro anti-metastatic effects on pancreatic cancer cells
title_sort discovery of novel small molecule inhibitors of s100p with in vitro anti-metastatic effects on pancreatic cancer cells
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501730/
https://www.ncbi.nlm.nih.gov/pubmed/32707527
http://dx.doi.org/10.1016/j.ejmech.2020.112621
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