Advanced chemical space exploration for the discovery of mutant-selective EGFR inhibitors

Acquired resistance remains the central challenge for targeted therapies in non-small cell lung cancer (NSCLC). While first-, second-, and third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have transformed treatment of classical EGFR mutations (L858R, Exon 19 deletions), tumors frequently escape therapy by acquiring additional mutations in the kinase domain. The combination of T790M and C797S resistance mutations is particularly severe, producing an EGFR variant resistant to every approved EGFR TKI.

Recent work by Schrödinger’s therapeutics group has shown how a structure-based, physics-driven design strategy can overcome this challenge, delivering structurally novel, potent, and mutant-selective inhibitors that spare wild-type EGFR and demonstrate efficacy in vivo, validating this computational workflow for some of the most difficult resistance mutations in oncology.

In this webinar, Schrödinger’s medicinal and computational chemists will show how they tackled the EGFR triple-mutant problem by coupling industry-leading free energy perturbation technology (FEP+) with de novo design workflows to effectively explore novel chemical space and identify reversible inhibitor scaffolds. The team will discuss how this multipronged strategy was used to rapidly navigate structure-activity relationships and deliver compounds with strong mutant potency, selectivity, and in vivo efficacy.