Abstract
Lung cancer is the first leading cause of death in human cancer, with 80-85% being non-small cell lung cancer (NSCLC). Over-expression of epidermal growth factor receptors (EGFR) is in 40-80% of NSCLC. Gefitinib (Iressa; AstraZeneca Pharmaceuticals) and erlotinib (Tarceva; Genentech, Inc.) were approved by U.S. Food and Drug Administration as EGFR kinase inhibitors for the treatment of adenocarcinoma (subtype of NSCLC). Gefitinib and erlotinib competitively bind to the ATP binding pocket of EGFR tyrosine kinase domain and inhibit its activity. These two drugs showed high response rates in specific subsets of NSCLC patients, but patients become resistant to treatment with gefitinib or erlotinib after 6-12 months. For approximately 50% of patients who respond initially to gefitinib or erlotinib, drug resistance occurs as a result of secondary mutation such as the Thr790 to Met790 (T790M) mutation. We designed and synthesized novel EGFR-TKIs, and expect that we can overcome the resistance issues for potential NSCLC therapy, and developed 2nd generation drugs.Through hybrid design and knowledge-based design concepts, (S)-phenyl-glycinol and Michael acceptor groups were introduced to high throughput hit 43 to obtain compounds 135, 150, 175 and 178 with 1~9 nM inhibition against wild type EGFR enzyme and EGFR overexpressed HCC827 NSCLC cell-line. This series also showed 10~305 nM inhibition against gefitinib-resistant double mutant EGFR (T790M/L858R) enzyme. More than 150 analogues based on compound 117 were synthesized, presence of (S)-phenyl-glycinol and Michael acceptor groups are essential for activity in this series of compounds and part of the results were published in J. Med. Chem., 2010, 53, 7316–7326.