Cargando…
Structure-activity exploration of a small-molecule allosteric inhibitor of T790M/L858R double mutant EGFR
EGFR is a protein kinase whose aberrant activity is frequently involved in the development of non-small lung cancer (NSCLC) drug resistant forms. The allosteric inhibition of this enzyme is currently one among the most attractive approaches to design and develop anticancer drugs. In a previous study...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9665079/ https://www.ncbi.nlm.nih.gov/pubmed/36373202 http://dx.doi.org/10.1080/14756366.2022.2145284 |
_version_ | 1784831216383426560 |
---|---|
author | Foschi, Francesca Tinivella, Annachiara Crippa, Valentina Pinzi, Luca Mologni, Luca Passarella, Daniele Rastelli, Giulio |
author_facet | Foschi, Francesca Tinivella, Annachiara Crippa, Valentina Pinzi, Luca Mologni, Luca Passarella, Daniele Rastelli, Giulio |
author_sort | Foschi, Francesca |
collection | PubMed |
description | EGFR is a protein kinase whose aberrant activity is frequently involved in the development of non-small lung cancer (NSCLC) drug resistant forms. The allosteric inhibition of this enzyme is currently one among the most attractive approaches to design and develop anticancer drugs. In a previous study, we reported the identification of a hit compound acting as type III allosteric inhibitor of the L858R/T790M double mutant EGFR. Herein, we report the design, synthesis and in vitro testing of a series of analogues of the previously identified hit with the aim of exploring the structure-activity relationships (SAR) around this scaffold. The performed analyses allowed us to identify two compounds 15 and 18 showing improved inhibition of double mutant EGFR with respect to the original hit, as well as interesting antiproliferative activity against H1975 NSCLC cancer cells expressing double mutant EGFR. The newly discovered compounds represent promising starting points for further hit-to-lead optimisation. |
format | Online Article Text |
id | pubmed-9665079 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-96650792022-11-15 Structure-activity exploration of a small-molecule allosteric inhibitor of T790M/L858R double mutant EGFR Foschi, Francesca Tinivella, Annachiara Crippa, Valentina Pinzi, Luca Mologni, Luca Passarella, Daniele Rastelli, Giulio J Enzyme Inhib Med Chem Brief Report EGFR is a protein kinase whose aberrant activity is frequently involved in the development of non-small lung cancer (NSCLC) drug resistant forms. The allosteric inhibition of this enzyme is currently one among the most attractive approaches to design and develop anticancer drugs. In a previous study, we reported the identification of a hit compound acting as type III allosteric inhibitor of the L858R/T790M double mutant EGFR. Herein, we report the design, synthesis and in vitro testing of a series of analogues of the previously identified hit with the aim of exploring the structure-activity relationships (SAR) around this scaffold. The performed analyses allowed us to identify two compounds 15 and 18 showing improved inhibition of double mutant EGFR with respect to the original hit, as well as interesting antiproliferative activity against H1975 NSCLC cancer cells expressing double mutant EGFR. The newly discovered compounds represent promising starting points for further hit-to-lead optimisation. Taylor & Francis 2022-11-13 /pmc/articles/PMC9665079/ /pubmed/36373202 http://dx.doi.org/10.1080/14756366.2022.2145284 Text en © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Brief Report Foschi, Francesca Tinivella, Annachiara Crippa, Valentina Pinzi, Luca Mologni, Luca Passarella, Daniele Rastelli, Giulio Structure-activity exploration of a small-molecule allosteric inhibitor of T790M/L858R double mutant EGFR |
title | Structure-activity exploration of a small-molecule allosteric inhibitor of T790M/L858R double mutant EGFR |
title_full | Structure-activity exploration of a small-molecule allosteric inhibitor of T790M/L858R double mutant EGFR |
title_fullStr | Structure-activity exploration of a small-molecule allosteric inhibitor of T790M/L858R double mutant EGFR |
title_full_unstemmed | Structure-activity exploration of a small-molecule allosteric inhibitor of T790M/L858R double mutant EGFR |
title_short | Structure-activity exploration of a small-molecule allosteric inhibitor of T790M/L858R double mutant EGFR |
title_sort | structure-activity exploration of a small-molecule allosteric inhibitor of t790m/l858r double mutant egfr |
topic | Brief Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9665079/ https://www.ncbi.nlm.nih.gov/pubmed/36373202 http://dx.doi.org/10.1080/14756366.2022.2145284 |
work_keys_str_mv | AT foschifrancesca structureactivityexplorationofasmallmoleculeallostericinhibitoroft790ml858rdoublemutantegfr AT tinivellaannachiara structureactivityexplorationofasmallmoleculeallostericinhibitoroft790ml858rdoublemutantegfr AT crippavalentina structureactivityexplorationofasmallmoleculeallostericinhibitoroft790ml858rdoublemutantegfr AT pinziluca structureactivityexplorationofasmallmoleculeallostericinhibitoroft790ml858rdoublemutantegfr AT mologniluca structureactivityexplorationofasmallmoleculeallostericinhibitoroft790ml858rdoublemutantegfr AT passarelladaniele structureactivityexplorationofasmallmoleculeallostericinhibitoroft790ml858rdoublemutantegfr AT rastelligiulio structureactivityexplorationofasmallmoleculeallostericinhibitoroft790ml858rdoublemutantegfr |