Discovery of a Potent and Orally Bioavailable Hypoxia-Inducible Factor 2α (HIF-2α) Agonist and Its Synergistic Therapy with Prolyl Hydroxylase Inhibitors for the Treatment of Renal Anemia

Activation of hypoxia-inducible factor
2 (HIF-2) has emerged as
a potent renal anemia treatment strategy. Here, the benzisothiazole
derivative 26 was discovered as a novel HIF-2α
agonist, which first demonstrated nanomolar activity (EC50 = 490 nM, Emax = 349.2%) in the luciferase
reporter gene assay. Molecular dynamics simulations indicated that 26 could allosterically enhance HIF-2 dimerization. Furthermore,
compound 26 had a good pharmacokinetic profile (the oral
bioavailability in rats was 41.38%) and an in vivo safety profile (the LD50 in mice was greater than 708
mg·kg–1). In the in vivo efficacy
assays, the combination of 26 and the prolyl hydroxylase
inhibitor, AKB-6548, was confirmed for the first time
to synergistically increase the plasma erythropoietin level in mice
(from 260 to 2296 pg·mL–1) and alleviate zebrafish
anemia induced by doxorubicin. These results provide new insights
for HIF-2α agonists and the treatment of renal anemia.

缺氧诱导因子2（HIF-2）的激活已成为治疗肾性贫血的有效策略。在此研究中，苯并异噻唑衍生物26被发现是一种新型的HIF-2α激动剂，其在荧光素酶报告基因检测中首次展现出纳米摩尔活性（EC50 = 490 nM，Emax = 349.2%）。分子动力学模拟表明，26可通过别构效应增强HIF-2二聚化。此外，化合物26具有良好的药代动力学特性（在鼠中的口服生物利用度为41.38%）和体内安全性特征（小鼠的LD50值大于708 mg·kg–1）。在体内疗效试验中，26与脯氨酰羟化酶抑制剂AKB-6548的联合应用首次证实能够协同提高小鼠血浆促红细胞生成素水平（从260 pg·mL–1升至2296 pg·mL–1），并缓解由阿霉素引起的斑马鱼贫血。这些研究结果为HIF-2α激动剂及其在肾性贫血治疗中的应用提供了新的见解。