4th Gen EGFR Inhibitor

T790M mutation is the most common mechanism of resistance to first- and second-generation tyrosine kinase inhibitors (TKI) for epidermal growth factor receptor (EGFR). Several third-generation EGFR mutant-selective TKIs are being explored to conquer this resistance. AZD9291 (osimertinib, TAGRISSO) has been approved for treatment of the metastatic EGFR T790M mutation-positive non-small cell lung cancer. Unfortunately, these lung cancer patients eventually developed resistance to these drugs after ten months. A better understanding of the mechanisms of resistance to these third-generation EGFR inhibitors is critical for developing new strategies to treat these patients. EGFR Cys797Ser(C797S) mutation, located within the tyrosine kinase domain, was recently reported to be a potential mechanism of resistance to irreversible EGFR inhibitors such as AZD9291, HM61713, WZ4002, and CO-1686 in T790M-positive patients (refer to the figure below). Therefore, the novel selective (4th generation) inhibitor overcoming the C797S mutant should be developed.
We are currently partnered with Yuhan Co to develop the 4th generation EGFR inhibitor-sparing wild type but potent to C797S mutant. It is in the lead optmization stage.