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SAF-248, a novel PI3K delta-selective inhibitor, potently suppresses the growth of diffuse large B-cell lymphoma

文献类型：期刊论文

作者Zhang, Xi1; Duan, Yu-ting1,2; Wang, Yi1; Zhao, Xing-dong3; Sun, Yi-ming1; Lin, Dong-ze1; Chen, Yi1,2; Wang, Yu-xiang1; Zhou, Zu-wen3; Liu, Yan-xin3
刊名ACTA PHARMACOLOGICA SINICA
出版日期2021-03-29
页码11
ISSN号1671-4083
关键词PI3Kδ PI3K AKT mTOR diffuse large B-cell lymphoma resistance combination therapy
DOI10.1038/s41401-021-00644-1
通讯作者Geng, Mei-yu(mygeng@simm.ac.cn) ; Ding, Jian(jding@simm.ac.cn) ; Meng, Ling-hua(lhmeng@simm.ac.cn)
英文摘要PI3K delta is expressed predominately in leukocytes and overexpressed in B-cell-related malignances. PI3K delta has been validated as a promising target for cancer therapy, and specific PI3K delta 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 PI3K delta inhibitor SAF-248, which exhibited high selectivity for PI3K delta (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 PI3K delta inhibitor idelalisib. In particular, SAF-248 potently inhibited the proliferation of a panel of seven DLBCL cell lines (with GI(50) values < 1 mu M 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 PI3K alpha. 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 PI3K delta inhibitor for the treatment of DLBCL and rational drug combination would further improve its efficacy.
资助项目Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020235] ; National Science and Technology Major Project Key New Drug Creation and Manufacturing Program[2018ZX09711002-004-004]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
出版者NATURE PUBLISHING GROUP
WOS记录号WOS:000634685300004
源URL[http://119.78.100.183/handle/2S10ELR8/295298]  
专题新药研究国家重点实验室
通讯作者Geng, Mei-yu; Ding, Jian; Meng, Ling-hua
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Medica, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Fochon Pharmaceut Ltd, Chongqing 404100, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Xi,Duan, Yu-ting,Wang, Yi,et al. SAF-248, a novel PI3K delta-selective inhibitor, potently suppresses the growth of diffuse large B-cell lymphoma[J]. ACTA PHARMACOLOGICA SINICA,2021:11.
APA Zhang, Xi.,Duan, Yu-ting.,Wang, Yi.,Zhao, Xing-dong.,Sun, Yi-ming.,...&Meng, Ling-hua.(2021).SAF-248, a novel PI3K delta-selective inhibitor, potently suppresses the growth of diffuse large B-cell lymphoma.ACTA PHARMACOLOGICA SINICA,11.
MLA Zhang, Xi,et al."SAF-248, a novel PI3K delta-selective inhibitor, potently suppresses the growth of diffuse large B-cell lymphoma".ACTA PHARMACOLOGICA SINICA (2021):11.

入库方式： OAI收割

来源：上海药物研究所

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