PI3Kδ is expressed predominately in leukocytes and overexpressed in B-cell-related malignances.PI3Kδ has been validated as a promising target for cancer therapy,and specific PI3Kδ inhibitors were approved for clinical practice.However,the substantial toxicity and relatively low efficacy as a monotherapy in diffuse large B-cell lymphoma(DLBCL)limit their clinical use.In this study,we described a novel PI3Kδ inhibitor SAF-248,which exhibited high selectivity for PI3Kδ(IC50=30.6 nM)over other PI3K isoforms at both molecular and cellular levels,while sparing most of the other human protein kinases in the kinome profiling.SAF-248 exhibited superior antiproliferative activity against 27 human lymphoma and leukemia cell lines compared with the approved PI3Kδinhibitor idelalisib.In particular,SAF-248 potently inhibited the proliferation of a panel of seven DLBCL cell lines(with Gl50 values＜1 μM in 5 DLBCL cell lines).We demonstrated that SAF-248 concentration-dependently blocked PI3K signaling followed by inducing G,phase arrest and apoptosis in DLBCL KARPAS-422,Pfeiffer and TMD8 cells.Its activity against the DLBCL cells was negatively correlated to the protein level of PI3Kα.Oral administration of SAF-248 dose-dependently inhibited the growth of xenografts derived from Pfeiffer and TMD8 cells.Activation of mTORC1,MYC and JAK/STAT signaling was observed upon prolonged treatment and co-targeting these pathways would potentiate the activity of SAF-248.Taken together,SAF-248 is a promising selective PI3Kδinhibitor for the treatment of DLBCL and rational drug combination would further improve its efficacy.

Xi Zhang;Yu-ting Duan;Yi Wang;Xing-dong Zhao;Yi-ming Sun;Dong-ze Lin;Yi Chen;Yu-xiang Wang;Zu-wen Zhou;Yan-xin Liu;Li-hua Jiang;Mei-yu Geng;Jian Ding;Ling-hua Meng

Division of Anti-tumor Pharmacology,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China;University of Chinese Academy of Sciences,Beijing 100049,China;Fochon Pharmaceuticals,Ltd.,Chongqing 404100,China;Division of Anti-Tumor Pharmacology,State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China

中国药理学报（英文版）

[1]Xi Zhang;Yu-ting Duan;Yi Wang;Xing-dong Zhao;Yi-ming Sun;Dong-ze Lin;Yi Chen;Yu-xiang Wang;Zu-wen Zhou;Yan-xin Liu;Li-hua Jiang;Mei-yu Geng;Jian Ding;Ling-hua Meng-.SAF-248,a novel PI3Kδ-selective inhibitor,potently suppresses the growth of diffuse large B-cell lymphoma)[J].中国药理学报（英文版）,2022(01):209-219

malignances,kinome,idelalisib,Gl50,KARPAS,TMD8

SAF,novel,PI3K,selective,potently,suppresses,growth,diffuse,large,lymphoma,predominately,leukocytes,overexpressed,been,validated,promising,cancer,specific,inhibitors,were,approved,clinical,practice,However,substantial,toxicity,relatively,efficacy,monotherapy,DLBCL,limit,their,In,this,study,described,which,exhibited,high,selectivity,IC50,nM,isoforms,both,molecular,cellular,levels,while,sparing,most,human,protein,kinases,profiling,superior,antiproliferative,activity,against,leukemia,lines,compared,particular,inhibited,proliferation,panel,seven,values,We,demonstrated,that,concentration,dependently,blocked,signaling,followed,by,inducing,phase,arrest,apoptosis,Pfeiffer,cells,Its,was,negatively,correlated,Oral,administration,dose,xenografts,derived,from,Activation,mTORC1,MYC,JAK,STAT,observed,upon,prolonged,treatment,targeting,these,pathways,would,potentiate,Taken,together,rational,drug,combination,further,improve,its

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