Synthesis and anti-tumor activity of pyrazole pyrimidine PI3Kγ/δ inhibitors
PI3Kγ and PI3Kδ have important regulatory roles in the immune system,and targeting these two subtypes helps to reshape the tumor microenvironment.PI3Kγ and PI3Kδ are potential targets for tumor immuno-therapy.In this study,a series of new pyrazolopyrimidine derivatives were designed and synthesized on the basis of our previously reported PI3K inhibitors,resulting in the discovery of compound 16l as a potent and selective PI3Kγ/δ dual inhibitor.Compound 16l demonstrated strong biochemical potencies against PI3Kγ and PI3Kδ with IC50 values of 0.11 and 0.79 nmol·L-1.In cell-based assays,it potently inhibited the PI3Kγ and PI3Kδ mediated Akt S473 phosphorylation with EC50 values of 3 and 7 nmol·L-1.In vivo,compound 16l exhibited acceptable pharmaco-kinetic properties in Sprague-Dawley(SD)rats and suppressed the tumor growth in a MC38 syngeneic mouse model.The animal experiments were approved by the Animal Ethics Committee of Hefei Institutes of Physical Science,Chinese Academy of Sciences(approval number:DWLL-2000-06).In addition,no appreciable human ether-a-go-go-related gene(hERG)inhibition was observed for compound 161 even at 30 μmol·L-1.These results suggested that compound 16l might be a potential research tool for studying the PI3Kγ/δ mediated signaling pathways.
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