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.