SAF-248,a novel PI3Kδ-selective inhibitor,potently suppresses the growth of diffuse large B-cell lymphoma
文献类型：期刊论文
| 作者 | Zhang Xi3; Duan Yuting3; Wang Yi3; Zhao Xingdong2; Sun Yiming3; Lin Dongze3; Chen Yi3 ; Wang Yuxiang3; Zhou Zuwen2; Liu Yanxin2
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| 刊名 | ACTA PHARMACOLOGICA SINICA
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| 出版日期 | 2022 |
| 卷号 | 43期号:1页码:209 |
| 关键词 | PI3K6 PI3K/AKT/mTOR diffuse large B-cell lymphoma resistance combination therapy |
| ISSN号 | 1671-4083 |
| 英文摘要 | 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 (IC_(50) = 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 PI3Kδ inhibitor 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_1 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 PI3Kδ inhibitor for the treatment of DLBCL and rational drug combination would further improve its efficacy. |
| 语种 | 英语 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/304833]  |
| 专题 | 中国科学院上海药物研究所 |
| 作者单位 | 1.中国科学院大学 2.Fochon Pharmaceuticals,Ltd. 3.Division of Anti-tumor Pharmacology,Shanghai Institute of Materia Medica,Chinese Academy of Sciences |
| 推荐引用方式 GB/T 7714 | Zhang Xi,Duan Yuting,Wang Yi,et al. SAF-248,a novel PI3Kδ-selective inhibitor,potently suppresses the growth of diffuse large B-cell lymphoma[J]. ACTA PHARMACOLOGICA SINICA,2022,43(1):209. |
| APA | Zhang Xi.,Duan Yuting.,Wang Yi.,Zhao Xingdong.,Sun Yiming.,...&Meng Linghua.(2022).SAF-248,a novel PI3Kδ-selective inhibitor,potently suppresses the growth of diffuse large B-cell lymphoma.ACTA PHARMACOLOGICA SINICA,43(1),209. |
| MLA | Zhang Xi,et al."SAF-248,a novel PI3Kδ-selective inhibitor,potently suppresses the growth of diffuse large B-cell lymphoma".ACTA PHARMACOLOGICA SINICA 43.1(2022):209. |
入库方式： OAI收割
来源：上海药物研究所
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