A novel class of irreversible EGFR kinase inhibitors, WZ4002 and related compounds, has been developed to selectively target the EGFR T790M mutation, a common resistance mechanism in EGFR mutant non-small cell lung cancer (NSCLC). These inhibitors are significantly more potent against EGFR T790M compared to quinazoline-based inhibitors, which are widely used but often cause toxicity due to their broad inhibition of wild-type EGFR. The new inhibitors show reduced potency against wild-type EGFR, making them more selective and potentially better tolerated. Structural studies revealed that these compounds form covalent bonds with Cys797 in EGFR, enhancing their potency and selectivity. In vitro and in vivo experiments demonstrated their effectiveness in lung cancer models driven by EGFR T790M, with significant tumor regression and reduced toxicity. Additionally, these inhibitors were effective in preventing the development of EGFR T790M in cells harboring activating mutations, suggesting their potential as initial therapy for EGFR mutant NSCLC. The crystal structure of WZ4002 in complex with EGFR T790M provided insights into the molecular basis of its selectivity and potency. These findings highlight the importance of functional pharmacological screens in identifying new classes of mutant-selective kinase inhibitors, which could lead to more effective and less toxic treatments for NSCLC.A novel class of irreversible EGFR kinase inhibitors, WZ4002 and related compounds, has been developed to selectively target the EGFR T790M mutation, a common resistance mechanism in EGFR mutant non-small cell lung cancer (NSCLC). These inhibitors are significantly more potent against EGFR T790M compared to quinazoline-based inhibitors, which are widely used but often cause toxicity due to their broad inhibition of wild-type EGFR. The new inhibitors show reduced potency against wild-type EGFR, making them more selective and potentially better tolerated. Structural studies revealed that these compounds form covalent bonds with Cys797 in EGFR, enhancing their potency and selectivity. In vitro and in vivo experiments demonstrated their effectiveness in lung cancer models driven by EGFR T790M, with significant tumor regression and reduced toxicity. Additionally, these inhibitors were effective in preventing the development of EGFR T790M in cells harboring activating mutations, suggesting their potential as initial therapy for EGFR mutant NSCLC. The crystal structure of WZ4002 in complex with EGFR T790M provided insights into the molecular basis of its selectivity and potency. These findings highlight the importance of functional pharmacological screens in identifying new classes of mutant-selective kinase inhibitors, which could lead to more effective and less toxic treatments for NSCLC.