GN44028

GN44028 is a hypoxia-inducible factor (HIF)-1α inhibitor with an IC₅₀ value of 14nM^[1-2]. GN44028 can be used in cancer research and has demonstrated the ability to enhance anticancer effects in the treatment of colorectal cancer^[3-4].

In vitro, BV2 microglial cells were pretreated with GN44028 (10μM) for 1 hour, followed by culture under hypoxic conditions (1% O₂). GN44028 significantly inhibited hypoxia-induced HIF-1α protein expression and downregulated the secretion of its downstream target gene Spp1^[5]. In human myoblasts adapted to chronic hypoxia (2% O₂, 3 weeks), pretreatment with GN44028 (1μM) for 48 or 96 hours significantly suppressed hypoxia-induced HIF-1α protein activity, reduced cell proliferation and glycolytic capacity, and impaired mitochondrial respiratory function (decreased OCR)^[6].

In vivo, BALB/c mice infected with Leishmania donovaniwere intraperitoneally administered GN44028 (10mg/kg body weight/day) starting from day 10 post-infection, with injections every 5 days until day 45. GN44028 significantly reduced parasitic loads in the spleen and liver and alleviated infection-associated immunopathology^[7]. In tumor-bearing mice (HCT116 or CT26 cells), GN44028 (5mg/kg) was administered via tail vein injection twice weekly from day 14 to day 60 post-cell inoculation. GN44028 significantly suppressed tumor growth, enhanced the chemotherapeutic effects of 5-fluorouracil (25mg/kg) and oxaliplatin (10mg/kg), and reduced the number of lung metastatic nodules^[8].

References:
[1] Shahruzaman SH, Fakurazi S, Maniam S. Targeting energy metabolism to eliminate cancer cells. Cancer Manag Res. 2018 Jul 31;10:2325-2335.
[2] Farina AR, Cappabianca L, Sebastiano M, et al. Hypoxia-induced alternative splicing: the 11th Hallmark of Cancer. J Exp Clin Cancer Res. 2020 Jun 15;39(1):110.
[3] Qannita RA, Alalami AI, Harb AA, et al. Targeting Hypoxia-Inducible Factor-1 (HIF-1) in Cancer: Emerging Therapeutic Strategies and Pathway Regulation. Pharmaceuticals (Basel). 2024 Feb 1;17(2):195.
[4] Yu T, Tang B, Sun X. Development of Inhibitors Targeting Hypoxia-Inducible Factor 1 and 2 for Cancer Therapy. Yonsei Med J. 2017 May;58(3):489-496.
[5] Bai Q, Wang X, Yan H, et al. Microglia-Derived Spp1 Promotes Pathological Retinal Neovascularization via Activating Endothelial Kit/Akt/mTOR Signaling. J Pers Med. 2023 Jan 11;13(1):146.
[6] Yin A, Fu W, Elengickal A, et al. Chronic hypoxia impairs skeletal muscle repair via HIF-2α stabilization. J Cachexia Sarcopenia Muscle. 2024 Apr;15(2):631-645.
[7] Roy S, Roy S, Halder S, et al. Leishmania exploits host cAMP/EPAC/calcineurin signaling to induce an IL-33-mediated anti-inflammatory environment for the establishment of infection. J Biol Chem. 2024 Jun;300(6):107366.
[8] Liu C, Zhang W, Wang J, et al. Tumor-associated macrophage-derived transforming growth factor-β promotes colorectal cancer progression through HIF1-TRIB3 signaling. Cancer Sci. 2021 Oct;112(10):4198-4207.

GN44028是一种缺氧诱导因子（HIF）-1α抑制剂，其IC₅₀值为14nM ^[1-2]。GN44028可用于癌症研究，在结直肠癌治疗中显示出增强抗癌效果的能力 ^[3-4]。

在体外，GN44028（10μM）预处理BV2小胶质细胞1小时，随后在低氧（1% O₂）条件下培养，GN44028显著抑制低氧诱导的HIF-1α蛋白表达，并下调其下游靶基因Spp1的分泌^[5]。GN44028（1μM）预处理适应低氧条件（2% O₂，3周）的人源成肌细胞48小时或96小时，GN44028显著抑制低氧诱导的HIF-1α蛋白活性，并降低细胞增殖率和糖酵解能力，同时削弱线粒体呼吸功能（OCR降低）^[6]。

在体内，GN44028（10mg/kg体重/天）腹腔注射处理感染Leishmania donovani的BALB/c小鼠（从感染后第10天开始，每5天一次，直至45天），GN44028显著降低脾脏和肝脏寄生虫负荷，并改善感染相关的免疫病理反应^[7]。GN44028（5mg/kg）尾静脉注射处理荷瘤（HCT116或CT26细胞）小鼠（每周两次，从接种细胞后第14天开始至60天），GN44028显著抑制肿瘤生长，增强5-氟尿嘧啶（25mg/kg）和奥沙利铂（10mg/kg）的化疗效果，并减少肺转移结节数量^[8]。