SD-233883

Head and neck squamous cell carcinomas (HNSCC) take many lifes worldwide. Patients with recurrent/metastatic disease receive combination chemotherapy containing anti-EGFR antibody cetuximab. However, resistance often hurdles therapy. The mechanism is yet to unveil, although EGFR extracellular alterations and activity of c-Met signaling were accused. We investigated the effects of EGFR-vIII and EGFR-R521K on cetuximab efficacy in HNSCC in cellular, xenograft, and clinical setup. Furthermore, we investigated the efficacy of c-Met inhibition in HNSCC in vitro and in vivo. We showed that EGFR-vIII is very rare in HNSCC, while the common R521K polymorphism abolishes antibody-dependent cellular cytotoxicity and in vivo antitumor effect of cetuximab. This selectivity was not reflected in immunophenotype or survival data of HNSCC patients, suggesting a more complex mechanism behind. Interestingly, c-Met inhibitor SU11274 was more effective in cetuximab-resistant, EGFR R521K heterozygous cells and xenografts, raising the possible importance of simultaneous targeting of the two receptors.

A new class of 2-amino-4-(1,2,4-triazol)pyridine derivatives were designed and synthesized as potent epidermal growth factor receptor inhibitors. In particular, compound 10c exhibited significant inhibitory against EGFR^L858R/T790M, and also displayed potent anti-proliferative activity against non-small cell lung cancer cell line H1975. Besides, compound 10j showed potent inhibitory activity against glioblastoma cell line U87-EGFRvⅢ, which was at least 3-fold more potent than Osimertinib and 25-fold superior to Lazertinib. Moreover, molecular modeling and molecular dynamics simulations disclosed the binding model of the most active compound to the domain of EGFR. This contribution provides 2-amino-4-(1,2,4-triazol)pyridines as a new scaffold for EGFR^T790M and/or EGFRvⅢ inhibitor.