Design,Synthesis,and Bioactivity Studies Of Novel ALK Small Molecule Inhibitors

Non-small cell lung cancer?NSCLC?is one of the major causes of cancer-related death in the world.In 2016,the incidence of NSCLC in China was 5%.Currently,the main method of treatment of lung cancer is molecular targeted therapy,including ALK,EGFR,C-Met and other targets.ALK as a new target for the treatment of lung cancer has made a breakthrough,has developed to the third generation of macrocyclic inhibitors.However,with the first ALK drug crizotinib marketed,patients developed resistance over two years.These resistance mainly include three kinds:First,changes in ALK genes such as"gatekeeper"mutations L1196M and common mutations C1156Y,insert mutations 1151Tins;the second is the ALK fusion gene amplification;third is the ALK signaling pathway Signal activation.At present,the third generation of ALK inhibitor is in phase II clinical stage.Although showing good selectivity and biological activity,the rapid emergence of resistance is far from enough.Therefore,there is still a need to find new inhibitors to address the emerging resistance.In this dissertation,ALK inhibitors were designed using computer-aided molecular design and virtual screening software?Sybyl-X 2.0?.The designed compounds were synthesized by chemical synthesis.A total of three batches of molecules were designed.The first batch was nine small molecules containing2,4-dichloro-R-pyrimidine as the nucleus and screening at the molecular level in vitro.The results showed that none of the nine target compounds had ALK The second batch is 13 compounds containing flexible chains with melamine as the nucleus and the activity data are still under test.The third batch contains 16 compounds containing rigid structure with cyanuric chloride as the core The 16 target compounds were all found to exhibit different degrees of ALK and EGFR inhibitory activity.Among them,the biological inhibitory activity of SLH3-6 and SLH3-11 all made breakthrough progress.In addition,the activities of EGFR?L858R/T790M?double mutation and C-Met of the compounds SLH-16 and SLH-20 were IC₅₀=2.567?m and IC₅₀=13.74?m,respectively.The work of this dissertation provides exploration experience and new research foundation for finding novel ALK small molecule inhibitors.