FL30: an epidermal growth factor kinase inhibitor overcoming T790M and C797S mutations through unique conformational modulation mechanism.

Tyrosine kinase inhibitors (TKIs) targeting the oncogene Epidermal Growth Factor Receptor (EGFR) are widely used in the treatment of non-small cell lung cancer (NSCLC). In this context, the introduction of fourth-generation TKIs has significantly advanced targeted therapy for T790M and C797S EGFR mutations. Current therapeutic strategies are increasingly focusing on the design of orthoallosteric TKIs, which have shown promise in stabilizing the inactive conformation of mutated EGFR. In this context, we report the discovery of FL30, a small molecule with a flavone core that exhibits nanomolar potency against the EGFR-L858R/T790M mutation, even in the presence of the C797S mutation. The IC comparable to the Osimertinib - one of the most renowned EGFR-TKIs - emphasizes the remarkable success of the design approach. In NSCLC models, FL30 effectively inhibits cancer growth and EGFR phosphorylation selectively in cells with the EGFR mutations. Kinetic studies, molecular modeling, and Plasmon Internal Reflection Surface-Enhanced Infrared Absorption (PIR-SEIRA) microscopy suggests that FL30 binds to the orthosteric site while inducing the transition of the mutant EGFR toward an inactive-like state. These findings highlight FL30's potential for further optimization and propose a novel approach for developing targeted therapies that combine orthosteric binding with allosteric modulation.