Balancing reactivity and antitumor activity: heteroarylthioacetamide derivatives as potent and time-dependent inhibitors of EGFR

Second- and third-generation inhibitors of EGFR possess an acrylamide group which alkylates Cys797, allowing to overcome resistance due to insurgence of T790M mutation. Less reactive warheads, yet capable to bind the target cysteine, may be useful to design newer and safer inhibitors. In the present...

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Published in:European journal of medicinal chemistry 2019-01, Vol.162, p.507-524
Main Authors: Castelli, Riccardo, Bozza, Nicole, Cavazzoni, Andrea, Bonelli, Mara, Vacondio, Federica, Ferlenghi, Francesca, Callegari, Donatella, Silva, Claudia, Rivara, Silvia, Lodola, Alessio, Digiacomo, Graziana, Fumarola, Claudia, Alfieri, Roberta, Petronini, Pier Giorgio, Mor, Marco
Format: Article
Language:English
Subjects:
4-Anilinoquinazoline
Cysteine
EGFR
QM/MM simulations
Time-dependent inhibition
Warhead
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Summary:Second- and third-generation inhibitors of EGFR possess an acrylamide group which alkylates Cys797, allowing to overcome resistance due to insurgence of T790M mutation. Less reactive warheads, yet capable to bind the target cysteine, may be useful to design newer and safer inhibitors. In the present work, we synthesized a 2-chloro-N-(4-(phenylamino)quinazolin-6-yl)acetamide (8) derivative as a prototype of EGFR inhibitor potentially able to react with Cys797 by nucleophilic substitution. We then tuned the reactivity of the acetamide fragment by replacing the chlorine leaving group with (hetero)-aromatic thiols or carboxylate esters. Among the synthesized derivatives, the 2-((1H-imidazol-2-yl)thio)acetamide 16, while showing negligible reactivity with cysteine in solution, caused long-lasting inhibition of wild-type EGFR autophosphorylation in A549 cells, resulted able to bind recombinant EGFR L858R/T790M in a time-dependent manner, and inhibited both EGFR autophosphorylation and proliferation in gefitinib-resistant H1975 lung cancer cells (expressing EGFR L858R/T790M mutant) at low micromolar concentration. [Display omitted] •A series of N-(4-(phenylamino)quinazolin-6-yl)acetamides was synthetized.•Imidazol-2-ylthioacetamide 16 causes long-lasting inhibition of EGFR.•16 shows negligible reactivity with cysteine in solution.•Biochemical assays suggest the formation of a covalent bond between 16 and Cys797.•Compound 16 inhibits proliferation of H1975 cells in the low micromolar range.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2018.11.029