SGI-1776 free base is an ATP-competitive Pim kinase inhibitor that inhibits the activity of Pim-1 (IC50=7nM), Pim-2 (IC50=363nM), and Pim-3 (IC50=69nM)[1]. SGI-1776 free base can trigger apoptosis by inducing G1 phase cell cycle arrest, activating Caspase-3, and reducing Mcl-1 protein levels[2]. SGI-1776 free base exhibits anti-tumor activity[3]. SGI-1776 free base has the ability to regulate lipid metabolism[4].
In vitro, treatment of chronic lymphocytic leukemia (CLL) primary cells with SGI-1776 free base (3–10μM) for 24–72 hours significantly induces apoptosis and inhibits global RNA synthesis by suppressing Pim kinase activity and reducing c-Myc (Ser62) phosphorylation levels[5]. Treatment of salivary adenoid cystic carcinoma cells (SACC-83 and SACC-LM) with SGI-1776 free base (2.5–5μM) for 72 hours significantly inhibits cell proliferation and induces G0/G1 and G2/M phase cell cycle arrest by suppressing Pim-1 protein expression and kinase activity. SGI-1776 free base reduces cell migration and invasion capabilities, induces mitochondrial membrane potential depolarization and caspase-3 activation, and promotes apoptosis[6].
In vivo, oral administration of SGI-1776 free base (75mg/kg) daily, five times per week for three weeks, to BALB/c-nu nude mice bearing ARK1 subcutaneous xenograft tumors significantly inhibits tumor growth[7]. Intraperitoneal injection of SGI-1776 free base (5mg/kg) once weekly, starting from 6 weeks of age, in wild-type or Ifnar1-/- C57BL/6 mice significantly suppresses Zika virus (ZIKV) replication in peritoneal macrophages of both mouse strains[8].
References:
[1] Chen LS, Redkar S, Taverna P, et al. Mechanisms of cytotoxicity to Pim kinase inhibitor, SGI-1776, in acute myeloid leukemia. Blood. 2011 Jul 21;118(3):693-702.
[2] Zhang X, Song M, Kundu JK, et al. PIM Kinase as an Executional Target in Cancer. J Cancer Prev. 2018 Sep;23(3):109-116.
[3] Yang Q, Chen LS, Neelapu SS, et al. Combination of Pim kinase inhibitor SGI-1776 and bendamustine in B-cell lymphoma. Clin Lymphoma Myeloma Leuk. 2013 Sep;13 Suppl 2(0 2):S355-62.
[4] Park YK, Hong VS, Lee TY, et al. The novel anti-adipogenic effect and mechanisms of action of SGI-1776, a Pim-specific inhibitor, in 3T3-L1 adipocytes. Int J Mol Med. 2016 Jan;37(1):157-64.
[5] Chen LS, Redkar S, Bearss D, et al. Pim kinase inhibitor, SGI-1776, induces apoptosis in chronic lymphocytic leukemia cells. Blood. 2009 Nov 5;114(19):4150-7.
[6] Hou X, Yu Y, Feng J, et al. Biochemical changes of salivary gland adenoid cystic carcinoma cells induced by SGI-1776. Exp Cell Res. 2017 Mar 15;352(2):403-411.
[7] Takeuchi H, Miyamoto T, Fuseya C, et al. PIM1 is a Poor Prognostic Factor for and Potential Therapeutic Target in Serous Carcinoma of the Endometrium. Int J Gynecol Pathol. 2023 May 1;42(3):282-292.
[8] Ren Y, Liu Y, Pang R, et al. ZIKV prM hijacks PIM1 kinase for phosphorylation to prevent ubiquitin-mediated degradation and facilitate viral replication. Front Cell Infect Microbiol. 2024 Nov 29;14:1502770.
SGI-1776 free base是一种ATP竞争性的Pim激酶抑制剂，可抑制Pim-1（IC50=7nM）、Pim-2（IC50=363nM）和Pim-3（IC50=69nM）的活性[1]。SGI-1776 free base可通过诱导G1期细胞周期停滞、激活Caspase-3以及降低Mcl-1蛋白水平来触发细胞凋亡[2]。SGI-1776 free base具有抗肿瘤活性[3]。SGI-1776 free base还具有调节脂肪代谢的能力[4]。
在体外，SGI-1776 free base（3–10μM）处理慢性淋巴细胞白血病（CLL）原代细胞24–72小时，SGI-1776 free base通过抑制Pim激酶活性及降低c-Myc（Ser62）磷酸化水平，显著诱导细胞凋亡并抑制全局RNA合成 [5]。SGI-1776 free base（2.5–5μM）处理唾液腺腺样囊性癌细胞（SACC-83及SACC-LM）72小时，SGI-1776 free base通过抑制Pim-1蛋白表达及激酶活性，显著抑制细胞增殖并诱导G0/G1期和G2/M期周期阻滞。SGI-1776 free base可降低细胞迁移和侵袭能力，诱导线粒体膜电位去极化及caspase-3活化，并促进细胞凋亡[6]。
在体内，SGI-1776 free base（75 mg/kg）每日口服给药，每周5次，持续3周，处理携带ARK1皮下异种移植瘤的BALB/c-nu裸鼠，SGI-1776 free base显著抑制肿瘤生长[7]。SGI-1776 free base（5mg/kg）每周一次腹腔注射，用于处理6周龄开始的野生型或Ifnar1-/- C57BL/6小鼠。SGI-1776显著抑制了ZIKV病毒在两种小鼠的腹腔巨噬细胞中的复制[8]。