SB 747651A dihydrochloride is a novel, orally active ATP-competitive inhibitor of mitogen- and stress-activated protein kinase 1 (MSK1; IC₅₀=11nM). SB 747651A dihydrochloride also effectively inhibits kinases such as PRK2, RSK1, p70S6K, and ROCK-II[1-2]. By suppressing RelA phosphorylation, SB 747651A dihydrochloride inhibits cancer cell invasion and is primarily used in research on inflammation and related immune disorders[3-4].
In vitro, SB 747651A dihydrochloride (1μM), either alone or in combination with cytarabine (Ara-C; 5μM), was applied to acute myeloid leukemia (AML) cell lines THP-1 and U937, as well as primary AML cells, for 24 hours. SB 747651A dihydrochloride significantly enhanced Ara-C-induced apoptosis, reduced cell viability, and induced cell cycle arrest at the G0/G1 phase, thereby increasing the chemosensitivity of AML cells to Ara-C[5]. SB 747651A dihydrochloride (2.5–20μM) pretreated human hepatoma HepG2-ADH cells for 4 hours, followed by ethanol (50mM) exposure for 2 hours. SB 747651A dihydrochloride significantly suppressed ethanol-induced Brf1 mRNA and protein expression, downregulated transcription of Brf1 downstream targets tRNALeu and 5S rRNA, and inhibited cell proliferation and colony formation in a dose- and time-dependent manner[6].
In vivo, SB 747651A dihydrochloride (25mg/kg/day) was administered intraperitoneally to tumor-bearing mice (implanted with T78 glioblastoma cells) five days a week for eight weeks, starting post-implantation. SB 747651A dihydrochloride significantly extended median survival and suppressed tumor growth[7]. SB 747651A dihydrochloride (5μM local perfusion or 3mg/kg intraperitoneal/intrathecal injection) was given to C57BL/6N mice subjected to CXCL2-induced inflammation. When administered 30 minutes before to 60 minutes after CXCL2 stimulation (or systemically 1 hour before CXCL2), SB 747651A dihydrochloride initially (1–2 hours) suppressed neutrophil transendothelial migration and tissue migration speed, but later (3–4 hours) promoted neutrophil extravasation and modulated Mac-1 integrin-dependent intravascular crawling[8].
References:
[1] Naqvi S, Macdonald A, McCoy CE, et al. Characterization of the cellular action of the MSK inhibitor SB-747651A. Biochem J. 2012 Jan 1;441(1):347-57.
[2] Bhat N, Park J, Zoghbi HY, et al. The Chromatin Modifier MSK1/2 Suppresses Endocrine Cell Fates during Mouse Pancreatic Development. PLoS One. 2016 Dec 14;11(12):e0166703.
[3] Johnson J, Shi Z, Liu Y, et al. Inhibitors of NF-kappaB reverse cellular invasion and target gene upregulation in an experimental model of aggressive oral squamous cell carcinoma. Oral Oncol. 2014 May;50(5):468-77.
[4] Zhao C, Hui W, Fernandes MJ, et al. Lysophosphatidic acid-induced IL-8 secretion involves MSK1 and MSK2 mediated activation of CREB1 in human fibroblast-like synoviocytes. Biochem Pharmacol. 2014 Jul 1;90(1):62-72.
[5] Zhang S, Pan C, Shang Q, et al. Overexpressed mitogen-and stress-activated protein kinase 1 promotes the resistance of cytarabine in acute myeloid leukemia through brahma related gene 1-mediated upregulation of heme oxygenase-1. Eur J Pharmacol. 2022 Feb 15;917:174722.
[6] Lin M, Huang C, Ren W, et al. Mitogen- and Stress-Activated Protein Kinase 1 Mediates Alcohol-Upregulated Transcription of Brf1 and tRNA Genes to Cause Phenotypic Alteration. Oxid Med Cell Longev. 2020 Jun 27;2020:2067959.
[7] Knudsen AM, Boldt HB, Jakobsen EV, et al. The multi-target small-molecule inhibitor SB747651A shows in vitro and in vivo anticancer efficacy in glioblastomas. Sci Rep. 2021 Mar 16;11(1):6066.
[8] Hossain M, Omran E, Xu N, et al. The Specific Mitogen- and Stress-Activated Protein Kinase MSK1 Inhibitor SB-747651A Modulates Chemokine-Induced Neutrophil Recruitment. Int J Mol Sci. 2017 Oct 17;18(10):2163.
SB 747651A dihydrochloride是一种新型的、具有口服活性的ATP竞争性丝裂原和应激激活激酶1（MSK1；IC₅₀=11nM）抑制剂。SB 747651A dihydrochloride还能有效抑制PRK2、RSK1、p70S6K和ROCK-II等激酶[1-2]。SB 747651A dihydrochloride可通过RelA的磷酸化抑制癌细胞的侵袭，SB 747651A dihydrochloride主要被用于炎症及相关免疫性疾病的研究[3-4]。
在体外，SB 747651A dihydrochloride（1μM）单独或联合阿糖胞苷（Ara-C；5μM）处理急性髓系白血病（AML）细胞系THP-1、U937及原代AML细胞24小时，SB 747651A dihydrochloride显著增强Ara-C诱导的细胞凋亡，并降低细胞活力；同时，SB 747651A dihydrochloride使细胞周期阻滞在G0/G1期，增强AML细胞对Ara-C的化疗敏感性[5]。SB 747651A dihydrochloride（2.5-20μM）预处理人肝癌HepG2-ADH细胞4小时，随后用乙醇（50mM）处理2小时，SB 747651A dihydrochloride显著抑制乙醇诱导的Brf1 mRNA和蛋白表达，并下调Brf1下游tRNALeu和5S rRNA的转录水平。SB 747651A dihydrochloride以剂量和时间依赖方式抑制细胞增殖和集落形成能力[6]。
在体内，SB 747651A dihydrochloride（25mg/kg/day）腹腔注射处理荷瘤（T78胶质母细胞瘤细胞）小鼠（从肿瘤植入后开始，每周5天，持续8周），SB 747651A dihydrochloride显著延长荷瘤小鼠的中位生存期，并减少肿瘤生长[7]。SB 747651A dihydrochloride（5μM灌注或3mg/kg腹腔/鞘内注射）处理CXCL2诱导炎症的C57BL/6N小鼠（在CXCL2刺激前30分钟至刺激后60分钟灌注给药，或CXCL2注射前1小时全身给药）SB 747651A dihydrochloride早期（1–2小时）抑制中性粒细胞跨内皮迁移和组织迁移速度，但晚期（3–4小时）促进中性粒细胞渗出，并调节整合素Mac-1依赖的血管内爬行[8]。