A sulfonyl fluoride derivative inhibits EGFR L858R/T790M/C797S by covalent modification of the catalytic lysine.

Autor: Ferlenghi F; Department of Food and Drug, University of Parma, Parma, Italy., Scalvini L; Department of Food and Drug, University of Parma, Parma, Italy., Vacondio F; Department of Food and Drug, University of Parma, Parma, Italy., Castelli R; Department of Food and Drug, University of Parma, Parma, Italy., Bozza N; Department of Food and Drug, University of Parma, Parma, Italy., Marseglia G; Department of Food and Drug, University of Parma, Parma, Italy., Rivara S; Department of Food and Drug, University of Parma, Parma, Italy., Lodola A; Department of Food and Drug, University of Parma, Parma, Italy. Electronic address: alessio.lodola@unipr.it., La Monica S; Department of Medicine and Surgery, University of Parma, Parma, Italy., Minari R; Medical Oncology, University Hospital of Parma, Parma, Italy., Petronini PG; Department of Medicine and Surgery, University of Parma, Parma, Italy., Alfieri R; Department of Medicine and Surgery, University of Parma, Parma, Italy., Tiseo M; Department of Medicine and Surgery, University of Parma, Parma, Italy; Medical Oncology, University Hospital of Parma, Parma, Italy., Mor M; Department of Food and Drug, University of Parma, Parma, Italy.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2021 Dec 05; Vol. 225, pp. 113786. Date of Electronic Publication: 2021 Aug 27.
DOI: 10.1016/j.ejmech.2021.113786
Abstrakt: The emergence of the C797S mutation in EGFR is a frequent mechanism of resistance to osimertinib in the treatment of non-small cell lung cancer (NSCLC). In the present work, we report the design, synthesis and biochemical characterization of UPR1444 (compound 11), a new sulfonyl fluoride derivative which potently and irreversibly inhibits EGFR L858R/T790M/C797S through the formation of a sulfonamide bond with the catalytic residue Lys745. Enzymatic assays show that compound 11 displayed an inhibitory activity on EGFR WT comparable to that of osimertinib, and it resulted more selective than the sulfonyl fluoride probe XO44, recently reported to inhibit a significant part of the kinome. Neither compound 11 nor XO44 inhibited EGFR del19/T790M/C797S triple mutant. When tested in Ba/F3 cells expressing EGFR L858R/T790M/C797S , compound 11 resulted significantly more potent than osimertinib at inhibiting both EGFR autophosphorylation and proliferation, even if the inhibition of EGFR autophosphorylation by compound 11 in Ba/F3 cells was not long lasting.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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