A sulfonyl fluoride derivative inhibits EGFRL858R/T790M/C797S by covalent modification of the catalytic lysine

Francesca Ferlenghi; Laura Scalvini; Federica Vacondio; Riccardo Castelli; Nicole Bozza; Giuseppe Marseglia; Silvia Rivara; Alessio Lodola; Silvia La Monica; Roberta Minari; Pier Giorgio Petronini; Roberta Alfieri; Marcello Tiseo; Marco Mor

doi:10.1016/j.ejmech.2021.113786

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

Eur J Med Chem. 2021 Dec 5:225:113786. doi: 10.1016/j.ejmech.2021.113786. Epub 2021 Aug 27.

Affiliations

¹ Department of Food and Drug, University of Parma, Parma, Italy.
² Department of Food and Drug, University of Parma, Parma, Italy. Electronic address: alessio.lodola@unipr.it.
³ Department of Medicine and Surgery, University of Parma, Parma, Italy.
⁴ Medical Oncology, University Hospital of Parma, Parma, Italy.
⁵ Department of Medicine and Surgery, University of Parma, Parma, Italy; Medical Oncology, University Hospital of Parma, Parma, Italy.

PMID: 34464874
DOI: 10.1016/j.ejmech.2021.113786

Abstract

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.

Keywords: C797S; Covalent inhibitor; EGFR; HRMS; Lysine; Osimertinib; Sulfonyl fluoride.

MeSH terms

Animals
Biocatalysis
Cell Proliferation / drug effects
Cell Survival / drug effects
Cells, Cultured
Dose-Response Relationship, Drug
ErbB Receptors / antagonists & inhibitors
ErbB Receptors / genetics
ErbB Receptors / metabolism
Humans
Lysine / antagonists & inhibitors*
Lysine / metabolism
Mice
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship
Sulfinic Acids / chemical synthesis
Sulfinic Acids / chemistry
Sulfinic Acids / pharmacology*

Substances

Protein Kinase Inhibitors
Sulfinic Acids
sulfuryl fluoride
EGFR protein, human
ErbB Receptors
Lysine