Design,Synthesis And Biological Activity Evaluation Of RET Fusion Kinase New Inhibitors

The RET(The Rearranged during Transfection)proto-oncogene is located on the 10th autosomal long arm(10q11.2)and encodes a transmembrane protein-the RET protein which belongs to the receptor tyrosine kinase family(Receptor Tyrosine Kinase,RTK).The mutations and recombinations of the RET proto-oncogenes are closely related to the occurrence and development of various diseases and tumor invasiveness,among which the common fused-genes are CCDC6-RET,KIF5B-RET,NCOA4-RET,and so on.The RET receptor proteins are potential drug targets for a wide variety of cancers.Even though some small molecule inhibitors can suppress RET mutations and fusions,their efficacy and selectivities need to be promoted.In this thesis,we are going to develop new RET kinase inhibitors with potent activities and high selectivity.Using NVP-BHG-712 as the lead compound,we have designed and synthesized a focus compound library targeting KIF5B-RET and CCDC6-RET.The core scafflods were pyrimidine and purine,and the key fragment for bioactivity of ponatinb was introduced.A total of 80 compounds were designed and synthesized.Their bioactivities were evaluated using a differential cytotoxicity assay against CCDC6-RET and KIF5B-RET transformed Ba/F3 cells.Structure activity relationship(SAR)study revealed that compounds,I-13,I-15,II-6,V-2,V-3 and V-7,exhibited the similar activity of Cabozantinib with IC50 values ranged in 0.1-0.2pM.Meanwhile,compounds ?-19,?-29,?-4,?-4,?-6 and V-4,shown better activities compared with Cabozantinib.Nitrogen methylpiperazine and 4-pyridine were found to be key structure features for having good activities.In summary,we have develop a series of small-molecule inhibitors targeting fused-kinases KIF5B-RET and CCDC6-RET with high activity and high selectivity.These results lay the foundation for further development of RET targeted drugs which has the potential to provide new solutions for cancer treatment.