Design,synthesis And Optimization Of The FGFR/RET Dual-target Inhibitors

Receptor tyrosine kinases（RTKs）are the important target of anti-tumor drugs,and most of the anti-tumor clinical drugs in market are RTKs inhibitors.According to the development of anti-tumor biology,pharmacologist found that FGFR and RET are crucial members of RTKs.As two important molecule targets,they are muture oncogenes of lung cancer and thyroid carcinoma respectively in clinical precise treatment.This dissertation based on our lab’s previous work,45 FGFR/RET inhibitors were designed and synthesized and they were under a careful scrutiny of structure-activity relationships（SARs）investigation.Based on the bioactivity screening in molecule level,we selected the compounds with a good inhibition against FGFR and RET kinases to test their bioactivities in cellular level.For the compounds with good bioactivity in vitro,we investigated its’pharmacokinetics（PK）properties in order to have a thorogh consideration of whether the compound deserved to be test in vivo.After the SARs investigation,we found compound 33 have a good bioactivity in molecule and cell level,but its’PK profile is poor,with low AUC and bioavailability.The vivo experiment elucidated that compound 33(C₃₁H₃₁F₃N₇O)can restrain the tumor growth in high dose,but also caused some rats to death.After compared the PK profiles of several compounds,we found that the pyridine part strruture have a great influence on PK profile.Then we evaluated compound4(C₂₇H₂₅ClF₃N₅O)’s PK property,which is better than Ponatinib,with high AUC level and bioavailability.The test in vivo showed that compound 4 can totally suppress the FGFR1-driven NCI-H1581 tumor’s growth at 50mg/kg,with the relative tumor proliferation of 3.77%,and no mice died during the whole experimental process.Based on the drugability-structure relationship,we reconsidered compound 4 as the lead compound,and the second-round optimization was launched to confirm that the N-methyl peperazine is the essential for the dual-target activity and the benzene ring in middle can tolerate the substituent group.Finally we got compound 37(C₂₇H₂₆F₃N₅O)with high bioactivity and good PK profile,and the evaluation in vivo is in progress.In summary,this dissertation designed and synthesized a series of novel FGFR/RET dual-target inhibitors.Conducted a particular SAR investigation and druggability exploration.And finally discovered compound 37,which have a remarkable anti-tumor activity and good PK profile.This work set up a good foundation for the developmemt of new medicine in cancer.