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.

Foschi, F., Tinivella, A., Crippa, V., Pinzi, L., Mologni, L., Passarella, D., et al. (2023). Structure-activity exploration of a small-molecule allosteric inhibitor of T790M/L858R double mutant EGFR. JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 38(1), 239-245 [10.1080/14756366.2022.2145284].

Structure-activity exploration of a small-molecule allosteric inhibitor of T790M/L858R double mutant EGFR

Crippa, Valentina;Mologni, Luca;
2023

Abstract

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.
Articolo in rivista - Articolo scientifico
allosteric inhibitors; anticancer drugs; drug design; EGFR inhibitors;
English
13-nov-2022
2023
38
1
239
245
none
Foschi, F., Tinivella, A., Crippa, V., Pinzi, L., Mologni, L., Passarella, D., et al. (2023). Structure-activity exploration of a small-molecule allosteric inhibitor of T790M/L858R double mutant EGFR. JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 38(1), 239-245 [10.1080/14756366.2022.2145284].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/432178
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