BAY 87-2243

BAY 87-2243 is a highly potent and selective inhibitor of hypoxia-inducible factor-1 (HIF-1)^[1]. HIF-1 is a transcription factor that regulates cellular responses to low oxygen environments and participates in biological processes such as angiogenesis, cell survival, glucose metabolism, and invasion through the activation of genes related to hypoxia adaptation^{[2, 3]}. BAY 87-2243 is often used in combination with radiotherapy or targeted agents in the treatment and research of melanoma, hepatocellular carcinoma, and head and neck squamous cell carcinoma^{[4, 5, 6]}.

In vitro, treatment of H460 cells with BAY 87-2243 (10, 100, 1000nM) for 16h significantly inhibited the mRNA expression of hypoxia-induced HIF target genes (CA9, Adrenomedullin (ADM), and Angiopoietin-like 4 (ANGPTL4)), while having no effect on the non-hypoxia-responsive gene EGLN2^[1]. Co-culture of CD4⁺T cells purified from rats with an experimental autoimmune myasthenia gravis (EAMG) inflammation model with BAY 87-2243 (1μM) for 48h reduced the proportions of Th1, Th17, and Th1/17 cells, increased the proportion of Treg cells, and decreased the concentrations of IFN-γ, IL-17, and IL-6 in the culture supernatant^[7].

In vivo, oral administration of BAY 87-2243 (9 mg/kg; once daily) for just 3 days to nude mice bearing UT-SCC-5 xenografts significantly reduced the pimonidazole hypoxia fraction (pHF) and the necrosis fraction (NF) in the tumors. Treatment for 5 and 7 days also significantly decreased the relative vascular area (RVA)^[6]. Alternate-day oral treatment with BAY 87-2243 (4mg/kg) for 28 days in mice bearing PMP xenografts significantly reduced MUC2 mRNA and protein expression levels in tumor tissue and inhibited the growth of mucinous tumors^[8].

References:
[1] ELLINGHAUS P, HEISLER I, UNTERSCHEMMANN K, et al. BAY 87-2243, a highly potent and selective inhibitor of hypoxia-induced gene activation has antitumor activities by inhibition of mitochondrial complex I[J]. Cancer Medicine, 2013, 2(5): 611-624.
[2] SEMENZA G L. Targeting HIF-1 for cancer therapy[J]. Nature Reviews Cancer, 2003, 3(10): 721-732.
[3] ADAMS J, DIFAZIO L, ROLANDELLI R, et al. HIF-1: a key mediator in hypoxia[J]. Acta Physiologica Hungarica, 2009, 96(1): 19-28.
[4] SCHÖCKEL L, GLASAUER A, BASIT F, et al. Targeting mitochondrial complex I using BAY 87-2243 reduces melanoma tumor growth[J]. Cancer & Metabolism, 2015, 3(1): 11.
[5] LI Y L, RAO M J, ZHANG N Y, et al. BAY 87-2243 sensitizes hepatocellular carcinoma Hep3B cells to histone deacetylase inhibitors treatment via GSK-3β activation[J]. Experimental and Therapeutic Medicine, 2019, 17(6): 4547-4553.
[6] HELBIG L, KOI L, BRÜCHNER K, et al. BAY 87-2243, a novel inhibitor of hypoxia-induced gene activation, improves local tumor control after fractionated irradiation in a schedule-dependent manner in head and neck human xenografts[J]. Radiation Oncology, 2014, 9(1): 207.
[7] YU L, RAN H, LU Y, et al. Targeting HIF-1α alleviates the inflammatory responses and rebuilds the CD4+ T cell subsets balance in the experimental autoimmune myasthenia gravis inflammation model via regulating cellular and humoral immunity[J]. Life Sciences, 2024, 336: 122287.
[8] DILLY A K, LEE Y J, ZEH H J, et al. Targeting hypoxia-mediated mucin 2 production as a therapeutic strategy for mucinous tumors[J]. Translational Research, 2016, 169: 19-30.

BAY 87-2243是一种具有高效选择性的缺氧诱导因子-1（HIF-1）抑制剂^[1]。HIF-1是调节细胞应对低氧环境的转录因子，它通过激活与缺氧适应相关的基因参与血管生成、细胞存活、葡萄糖代谢和侵袭等生物进程^[2,3]。BAY 87-2243通常与放疗或靶向药物联合针对黑色素瘤、肝细胞癌及头颈部鳞癌进行治疗和研究^[4,5,6]。

在体外，BAY 87-2243（10, 100, 1000nM）处理H460细胞16h，能显著抑制缺氧诱导的HIF靶基因（CA9，肾上腺髓质素（ADM）和血管生成素样蛋白-4（ANGPTL4））mRNA表达，而对非缺氧响应基因EGLN2无影响^[1]。BAY 87-2243（1μM）与从实验性自身免疫重症肌无力（EAMG）炎症模型大鼠中纯化的CD4⁺T细胞共培养48h，降低了Th1、Th17和Th1/17细胞的比例，增加了Treg细胞的比例，并减少了培养上清液中IFN-γ、IL-17和IL-6的浓度^[7]。

在体内，BAY 87-2243（9mg/kg; once daily）通过口服处理携带UT-SCC-5异种移植瘤的裸鼠3天，即可显著降低肿瘤的哌莫硝唑缺氧分数（pHF），并减少坏死分数（NF）。处理5天和7天时，还能显著降低相对血管面积（RVA）^[6]。BAY 87-2243（4mg/kg）通过隔日口服治疗携带PMP异种移植瘤的小鼠28天，显著降低了肿瘤组织中MUC2 mRNA和蛋白的表达水平，抑制了黏液性肿瘤的生长^[8]。