Biomedical Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
ASCA Company, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
Expert Opin Ther Pat. 2021 May;31(5):387-397. doi: 10.1080/13543776.2021.1874345. Epub 2021 Jan 29.
: Hypoxia-inducible factor (HIF) is a master regulator of oxygen homeostasis. The increased expression of genes targeted by HIF is associated with many human diseases, including ischemic cardiovascular disease, stroke, chronic lung disease, and cancer.: This patent survey summarizes the information about patented HIF inhibitors over the last 5 years.: HIF inhibitors have shown promise for the treatment of hypoxic pulmonary hypertension, a circadian rhythm disorder, calcific aortic valve disease, cerebrovascular accident, and heterotopic ossification. In addition, HIF-2α inhibitors can be used for the treatment or prevention of iron overload disorders, Crohn's disease, ulcerative colitis, and thyroid eye disease, or to improve muscle generation and repair. PT2385 completed phase I clinical trials for the treatment of clear cell renal cell carcinoma. It exerted a higher synergistic inhibitory effect on tumor growth in combination with anti-PD-1 antibody, in comparison with each treatment alone, indicating that effective immunotherapy for solid tumors counteracts of the immunosuppression induced by hypoxia. Therefore, considering the effects of hypoxia on cancer cells, stromal cells, and effector immune cells, it is important to develop inhibitors of molecular pathways activated by hypoxia for successful treatments.
缺氧诱导因子 (HIF) 是氧平衡的主要调节因子。HIF 靶向基因的表达增加与许多人类疾病有关，包括缺血性心血管疾病、中风、慢性肺部疾病和癌症。
本专利调查总结了过去 5 年中已获得专利的 HIF 抑制剂的信息。
HIF 抑制剂在治疗低氧性肺动脉高压、昼夜节律紊乱、钙化性主动脉瓣疾病、中风和异位骨化方面显示出良好的疗效。此外，HIF-2α抑制剂可用于治疗或预防铁过载疾病、克罗恩病、溃疡性结肠炎和甲状腺眼病，或改善肌肉生成和修复。PT2385 已完成用于治疗肾透明细胞癌的 I 期临床试验。与单独治疗相比，它与抗 PD-1 抗体联合使用对肿瘤生长具有更高的协同抑制作用，这表明有效的实体瘤免疫疗法可以对抗由缺氧引起的免疫抑制。因此，考虑到缺氧对癌细胞、基质细胞和效应免疫细胞的影响，开发由缺氧激活的分子途径抑制剂对于成功治疗至关重要。
