一种新型PI3K抑制剂JN-65的抗肿瘤活性及其分子模拟机制研究

柯珂; 蒋雯丽; 王雨; 朱景宇; 金坚

doi:10.11665/j.issn.1000-5048.20190405

一种新型PI3K抑制剂JN-65的抗肿瘤活性及其分子模拟机制研究

江南大学药学院药物设计与分子药理学实验室

基金项目: 国家自然科学基金资助项目(No.21807049)

计量
- 文章访问数: 564
- HTML全文浏览量: 0
- PDF下载量: 1590
出版历程
- 刊出日期: 2019-08-24

Study on the bioactivity against hematologic malignancies and theoretical binding mechanism of a novel PI3K inhibitor JN-65

摘要

摘要: 在恶性血液肿瘤中，PI3K信号通路往往呈现过度表达的紊乱状态，开发PI3K抑制剂治疗恶性血液肿瘤具有广阔的应用前景。本研究通过恶性血液肿瘤的特异性筛选，得到了一个PI3K靶向抑制剂JN-65。MTT检测发现JN-65可以有效抑制血液肿瘤的增殖，其中对白血病细胞特异性较强。体外酶活性检测发现JN-65对PI3K具有一定的抑制活性且对PI3Kγ表现出较强的选择性抑制作用，Western blot实验表明，JN-65能有效抑制PI3K/Akt信号通路，细胞流式实验证明，JN-65通过抑制PI3K信号通路有效地诱导肿瘤细胞的凋亡。本研究采用分子对接模拟方法研究JN-65与PI3K相互作用关系，在分子水平对PI3K的抑制机制进行了研究。JN-65有望成为一个潜在的PI3K抑制剂，能特异性地抑制恶性血液肿瘤。
- PI3K抑制剂 /
- JN-65 /
- 恶性血液肿瘤 /
- 白血病 /
- 分子对接
Abstract: The PI3K signaling pathway is frequently over-expressed in a variety of hematologic malignancies, so the development of PI3K inhibitors for the treatment of hematologic malignancies has broad application prospects. In this study, a novel PI3K inhibitor, JN-65, was identified through the investigation effects in the inhibition to hematologic malignancies. By MTT assays, JN-65 was found to effectively suppress the proliferation of hematologic malignancies, especially leukemia cell lines. The cell-free enzymatic studies demonstrated that JN-65 cloud inhibit PI3K and specifically inhibited PI3Kγ at low micromolar concentrations. Western blot confirmed that JN-65 could effectively inhibit the PI3K/Akt signaling pathway and the flow cytometry assays verified that JN-65 could induce the apoptosis of tumor cells through the suppression of PI3K signaling pathway. Finally, the molecular docking simulation method was used to explore the interaction between JN-65 and PI3K, and the inhibition mechanism of PI3K was revealed at the molecular level. In general, JN-65 would be a potential PI3K inhibitor for the treatment of hematologic malignancies.
- PI3K inhibitor /
- JN-65 /
- hematologic malignancies /
- leukemia /
- molecular docking

HTML全文

参考文献(22)

[1]	Zhu JY,Wang M,Cao BY,et al.Targeting the phosphatidylinositol 3-kinase/AKT pathway for the treatment of multiple myeloma[J].Curr Med Chem,2014,21(27):3173-3187.
[2]	Naymagon L,Abdul-Hay M.Novel agents in the treatment of multiple myeloma:a review about the future[J].J Hematol Oncol,2016,9(1):52.
[3]	Zhu JY,Hou TJ,Mao XL.Discovery of selective phosphatidylinositol 3-kinase inhibitors to treat hematological malignancies[J].Drug Discov Today,2015,20(8):988-994.
[4]	Cantley LC.The phosphoinositide 3-kinase pathway[J].Science,2002,296(5573):1655-1657.
[5]	Fruman DA,Rommel C.PI3K and cancer:lessons,challenges and opportunities[J].Nat Rev Drug Discov,2014,13(2):140-156.
[6]	Carracedo A,Pandolfi PP.The PTEN-PI3K pathway:of feedbacks and cross-talks[J].Oncogene,2008,27(41):5527-5541.
[7]	Liu PX, Cheng HL, Roberts TM, et al. Targeting the phosphoinositide 3-kinase pathway in cancer[J].Nat Rev Drug Discov,2009,8(8):627-644.
[8]	Yuan TL,Cantley LC.PI3K pathway alterations in cancer:variations on a theme[J].Oncogene,2008,27(41):5497-5510.
[9]	Jiang BH, Liu LZ. PI3K/PTEN signaling in angiogenesis and tumorigenesis[J].Adv Cancer Res,2009,102:19-65.
[10]	Fresno Vara JA,Casado E,de Castro J,et al.PI3K/Akt signalling pathway and cancer[J].Cancer Treat Rev,2004,30(2):193-204.
[11]	Xin MH,Zhang SQ.Advances in PI3Kδ selective inhibitors[J].J China Pharm Univ(中国药科大学学报),2016,47(5):503-510.
[12]	Hennessy BT,Smith DL,Ram PT,et al.Exploiting the PI3K/AKT pathway for cancer drug discovery[J].Nat Rev Drug Discov,2005,4(12):988-1004.
[13]	Lien EC,Dibble CC,Toker A.PI3K signaling in cancer:beyond AKT[J].Curr Opin Cell Biol,2017,45:62-71.
[14]	Silva A,Yunes JA,Cardoso BA,et al.PTEN posttranslational inactivation and hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability[J].J Clin Invest,2008,118(11):3762-3774.
[15]	Min YH,Eom JI,Cheong JW,et al.Constitutive phosphorylation of Akt/PKB protein in acute myeloid leukemia:its significance as a prognostic variable[J].Leukemia,2003,17(5):995-997.
[16]	Hyun T,Yam A,Pece S,et al.Loss of PTEN expression leading to high Akt activation in human multiple myelomas[J].Blood,2000,96(10):3560-3568.
[17]	Miller BW,Przepiorka D,de Claro RA,et al.FDA approval:idelalisib monotherapy for the treatment of patients with follicular lymphoma and small lymphocytic lymphoma[J].Clin Cancer Res,2015,21(7):1525-1529.
[18]	Blair HA.Duvelisib:first global approval[J].Drugs,2018,78(17):1847-1853.
[19]	Miller MS,Maheshwari S,McRobb FM,et al.Identification of allosteric binding sites for PI3Kα oncogenic mutant specific inhibitor design[J].Bioorg Med Chem,2017,25(4):1481-1486.
[20]	Zhang XX,Vadas O,Perisic O,et al.Structure of lipid kinase p110β/p85β elucidates an unusual SH2-domain-mediated inhi-bitory mechanism[J].Mol Cell,2011,41(5):567-578.
[21]	Somoza JR,Koditek D,Villaseñor AG,et al.Structural,biochemical,and biophysical characterization of idelalisib binding to phosphoinositide 3-kinase δ[J].J Biol Chem,2015,290(13):8439-8446.
[22]	Pecchi S,Ni ZJ,Han W,et al.Structure guided optimization of a fragment hit to imidazopyridine inhibitors of PI3K[J].Bioorg Med Chem Lett,2013,23(16):4652-4656.

施引文献

资源附件(0)

计量

文章访问数: 564
HTML全文浏览量: 0
PDF下载量: 1590
被引次数: 0

一种新型PI3K抑制剂JN-65的抗肿瘤活性及其分子模拟机制研究

计量

出版历程

Study on the bioactivity against hematologic malignancies and theoretical binding mechanism of a novel PI3K inhibitor JN-65

计量

出版历程

目录