Design,Synthesis,and Antitumor Evaluation Of Novel Dual Pan-PI3K/mTOR Inhibitors

The PI3K-AKT-mTOR signaling pathway plays a crucial role in the key cellular functions,including cell survival,growth,proliferation,differentiation and apoptosis.Aberrant PI3K-AKT-mTOR signaling pathway activation has been shown in various malignancies.Therefore,PI3K pathway has become one of the important targets for cancer treatment.Only the pan-PI3K inhibitor Copanlisib and the Isoform-specific PI3K inhibitor Idelalisib were successfully marketed,while none of the Dual PI3K-mTOR inhibitors were approved for marketing.Therefore,it is particularly urgent to develop a Dual PI3K-mTOR inhibitor with sufficient clinical activity and low toxicity.With the assistance of computer aided drug design and related literature reports,a series of compounds with different linker structures?Series 1,Series 2 and Series 3?were designed and synthesized based on the structure of GSK2126458 using scaffold hopping and bioisosterism strategy.Through the study of SAR,compound PO-1023with a linker of 1,3,4-oxadiazole has a good inhibitory effect on both enzymatic and proliferation of various cancer cells.PO-1023 inhibited PI3K subtypes and mTOR kinase better than the marketed pan-PI3K inhibitor Copanlisib.In addition,the PO-1023 has a remarkable anti-proliferative activities against cancer cells?HCT116,HT-29,LOVO,MCF-7,A549,and PC-3?in vitro with an IC₅₀ of 5-89 nM.Subsequently,the SAR of the novel Dual Pan-PI3K/mTOR inhibitor PO-1023 was studied.The study showed that the linker's substituent is a hydrophilic group,which can significantly increase potency for kinase;The sulfonamide is an essential group for potency;When the substituent is 2,4-difluorophenyl,the kinase potency can be increased;When the substituent of the side chain of the pyridine ring is methoxy and chlorine,the kinase potency can be increased;The C-3 and C-6 positions of the imidazo[1,2-a]pyridine core are essential sites for potency.PO-1023 can effectively inhibit the growth of human colorectal cancer xenografts in nude mice,and the tumor growth inhibition rate?TGI?is 59.42%,which has significant anti-tumor activity in vivo.The half-life of PO-1023 in SD rats which were administered by intragastric administration was 7.94 h,and the relative bioavailability was 26.8%,indicating that the compounds have better pharmacokinetic parameters.In conclusion,PO-1023,a novel Dual PI3K-mTOR inhibitor,is a promising lead compound with good potential drug-forming properties and could be considered as a potential candidate for the development of anticancer agents.