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.

EGFR中C797S突变的出现是非小细胞肺癌（NSCLC）治疗中奥希替尼耐药的常见机制。在目前的工作中，我们报告了 UPR1444（化合物11 ）的设计、合成和生化表征，这是一种新的磺酰氟衍生物，它通过与催化残基 Lys745 形成磺酰胺键，有效且不可逆地抑制 EGFR ^{L858R/T790M/ C797S。}酶学分析表明，化合物11对 EGFR ^WT的抑制活性与奥希替尼相当，并且其结果比磺酰氟探针 XO44 更具选择性，最近报道该探针可抑制大部分激酶组。化合物11都不是nor XO44 抑制 EGFR ^{del19/T790M/C797S}三重突变体。当在表达 EGFR ^{L858R/T790M/C797S}的 Ba/F3 细胞中进行测试时，化合物11在抑制 EGFR 自身磷酸化和增殖方面比奥希替尼显着更有效，即使化合物11在 Ba/F3 细胞中对 EGFR 自身磷酸化的抑制不持久.