Novel Selective and Potent EGFR Inhibitor that Overcomes T790M Mediated Resistance in Non Small Cell Lung Cancer
Treating patients suffering from EGFR mutant non small cell lung cancer (NSCLC) with first generation EGFR tyrosine kinase inhibitors (EGFR TKI) provides excellent response rates. However, approximately 60% of all patients ultimately develop drug resistance due to a second T790M EGFR TKI mutation. In this study, we report the novel molecule N (3 (5 chloro 2 (4 (1 morpholino)methyl)phenylamino) 4 pyrimidinyl)amino)phenyl)acrylamide (DY3002) to preferentially inhibit the EGFR T790M mutant (EGFRT790M) (IC50 0.71 nM) over wild type EGFR (IC50 448.7 nM) in kinase assays. Compared to rociletinib (SI 21.4) and osimertinib (SI 40.9) it significantly increased selectivity (SI 632.0) against EGFRT790M over wild type EGFR. Furthermore, in cell based tests, DY3002, with an IC50 value of 0.037 mM, exhibited enhanced inhibitory potency against H1975 cells. Moreover, AO/EB and DAPI staining assays as well as flow cytometer analyses indicated that DY3002 possesses superior biological properties compared to alternatives. In addition, a rat oral glucose tolerance test revealed that treatment with high drug doses (50 mg/kg) of DY3002 did not result in hyperglycemia, suggesting a reduction of side effects in NSCLC patients will be achievable relative to established EGFR inhibitors. In summary, our findings indicate DY3002 as a promising preclinical candidate for effective treatment of patients with EGFRT790M mutated NSCLC.
Molecules