A sulfonyl fluoride derivative inhibits EGFR<sup>L858R/T790M/C797S</sup> by covalent modification of the catalytic lysine.
Ferlenghi F, Scalvini L, Vacondio F, Castelli R, Bozza N, Marseglia G, Rivara S, Lodola A, La Monica S, Minari R, Petronini PG, Alfieri R, Tiseo M, Mor M.
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<sup>L858R/T790M/C797S</sup> through the formation of a sulfonamide bond with the catalytic residue Lys745. Enzymatic assays show that compound 11 displayed an inhibitory activity on EGFR<sup>WT</sup> 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<sup>del19/T790M/C797S</sup> triple mutant. When tested in Ba/F3 cells expressing EGFR<sup>L858R/T790M/C797S</sup>, 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.