Design,Synthesis And Biological Evaluation Of Novel C-Met And PLK1 Inhibitors

c-Met and PLK1 kinase inhibitors play an important role in the development of new anti-tumor drugs.Two drugs targeted on c-Met have been launched,and many new chemical entities are on clinical trials.Most of PLK1 inhibitors are studied in pre-clinical and clinical stages,but none has been launched to market.So it is worth to design,synthesis and evaluation of novel c-Met and PLK1 inhibitors.In this study,131 new compounds in 8 species have been synthesized and then evaluated for antitumor acitivity and druggability.The promising compounds SIPI7228 and SIPI7067,possessing low toxicity,good PK properties,low hERG toxicity and potent antitumor activities,are worth to be further studied.1.Rational design of novel compoundsBased on the structure feathers and pharmacophores of reported compounds and launched drugs,new compounds were designed by scaffold transition and bioisosterism to remain the structural similarity.The binding mode of these compounds with corresponding target were analyzed by computer aided drug design software,and the design reasonability are verified through pharmacology activities,which is helpful to the subsequent compound design and optimization.2.Synthesis and chemical research of new compounds69 c-Met inhibitors and 62 PLK1 inhibitors were synthesized through brief and convenient synthetic routes based on retrosynthetic analysis,and the chemical structures were confirmed by MS and 1H-NMR spectroscopy.The key intermediates were also developed in detail aimed for preparing on a large scale and guiding the synthesis of analogues.3.Anti-tumor activities of new compounds3.1 Anti-tumor activities of c-Met inhibitorsIn series A,the IC50 values of compound SIPI7234 and SIPI7235 targeting c-Met were 236 and 275 nmol/L,and the anti-proliferative activities of compound SIPI7234 against Panc-1,HepG2,Caki-1 and HCT116 were equal to the positive control drug Cabozantinib.In series B,the IC50 value of compound SIPI7100 to c-Met was 137 nmol/L,which indicated that aminopyrimidine structure had good affinities to c-Met kinase to improve the activity.In series C,compounds SIPI7224,SIPI7228 and SIPI7239 exhibited approximately equal inhibitory activity with Cabozantinib,and the anti-proliferative activities were more potent than that of Cabozantinib.Finally,SIPI7228 was identified as a promising compound to be evaluated intensively for druggability properties.In series D,it is innovative to introduce tricyclic group as the pharmacophore scaffold.Among of compounds in this series,SIPI7064,SIPI7067,SIPI7076 and SIPI7077 showed moderate to excellent kinase inhibitory and anti-proliferative activities.Then,SIPI7067 was finally evaluated intensively for druggability properties.3.2 Anti-tumor activities of PLK1 inhibitorsCompounds SIPI7473,SIPI7475 and SIPI7915 displayed equal kinase inhibitory activities to Volasertib.Compound SIPI7491 revealed comparative and better anti-proliferative activities against HL-60 and THP-1 respectively than Volasertib.The anti-proliferative activities of compound SIPI7489 and SIPI7498 against THP-1 were also equal to Volasertib.The anti-proliferative activities of compound SIPI7482 and SIPI7916 against Hela cell were was five and ten times more active than that of SBE-13.The weak activities of series Ⅳ may be due to the high conservative of the structures.4.Prelimilary evaluation of druggability of compound SIPI7228 and SIPI7067The promising compound SIPI7228 and SIPI7067 was evaluated on druggability,such as MTD,PK,hERG and in vivo activity.The above evaluation indicated that compound SIPI7228 and SIPI7067 displayed favourable pharmacokinetic properties in rats,an acceptable safety profile in preclinical studies,and significant anti-tumour activity in the Caki-1 tumour xenograft model,which are worth for further study.The research enriched the structure types and SARs of c-Met and PLK1 inhibitors,and had laid the foundation of new active compounds design.The experience could provide some helpful reference for the new drug development based on the target of c-Met and PLK1.