Executive Summary : | On March 30, 2017, the UsFDA gave regular approval to Osimertinib (AZD9291) for the management of patients with metastatic EGFR-T790M NsCLC. Osimertinib (FDA-approved) is at the forefront clinically for the treatment of patients with Non-small Cell Lung Cancer (NsCLC). Osimertinib binds covalently to Cys797 and largely spares WT-EGFR, thereby decreasing toxicity and permitting the use of doses that fully suppress T790M. However, a high percentage of patients treated with Osimertinib (AZD9291) developed a tertiary cystein797 to serine790 (C797s) mutation in the EGFR kinase domain, rendering resistance to it. Additional studies with third generation cell lines have shown that the allelic context of the activating gatekeeper and C797s mutations affects the sensitivity to three generations of inhibitors with no EGFR TKIs alone or in combination, and is able to suppress activity when the mutation is in cis. This data suggests that there is a pressing need for drugs which can overcome the triple mutant L858R-T790M-C797s EGFR resistance obstacle in NsCLC associated with Osimertinib. In view of this justification, the current proposal deals with the design and synthesis of fourth generation triple mutant selective EGFR-L858R-T790M-C797s tyrosine kinase inhibitors to overcome the resistance obstacle in NsCLC chemotherapy. |