BREED based de novo hybridization approach: generating novel T790M/C797S-EGFR tyrosine kinase inhibitors to overcome the problem of mutation and resistance in non small cell lung cancer (NSCLC).

Third generation EGFR inhibitor osimertinib was approved as the first-line treatment for EGFR T790M mutation-positive Non-Small Cell Lung Cancer (NSCLC) patients in 2017. However, EGFR tertiary Cys797 to Ser797 (C797S) point mutation emanate rapidly after treatment of osimertinib, which is undruggable mutation to the all existing drugs. In this work, we have reported the novel T790M/C797S-EGFR Tyrosine Kinase inhibitors using BREED based de novo hybridization approach. BREED generates novel inhibitors from structures of known ligands bound to a common target. Among the generated hybridised breed compounds, the top best scorer breed molecules were breed 436, breed 530, breed 450, breed 562 and breed 313. Molecular Dynamics simulation of breed 436 for 10 ns further suggested that docked compound was stable into the pocket of the T790M/C797S-EGFR Tyrosine Kinase. In silico pharmacokinetic predictions of the breed hybridised compounds were within the defined range described for human use.Communicated by Ramaswamy H. Sarma.