Hypoxia-inducing transcription factors: architects of tumorigenesis and targets for anticancer drug discovery.

IF 3.6 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Ali Tavassoli, Alexander McDermott
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引用次数: 0

Abstract

Hypoxia-inducible factors (HIFs) play a pivotal role as master regulators of tumor survival and growth, controlling a wide array of cellular processes in response to hypoxic stress. Clinical data correlates upregulated HIF-1 and HIF-2 levels with an aggressive tumor phenotype and poor patient outcome. Despite extensive validation as a target in cancer, pharmaceutical targeting of HIFs, particularly the interaction between α and βsubunits that forms the active transcription factor, has proved challenging. Nonetheless, many indirect inhibitors of HIFs have been identified, targeting diverse parts of this pathway. Significant strides have also been made in the development of direct inhibitors of HIF-2, exemplified by the FDA approval of Belzutifan for the treatment of metastatic clear cell renal carcinoma. While efforts to target HIF-1 using various therapeutic modalities have shown promise, no clinical candidates have yet emerged. This review aims to provide insights into the intricate and extensive role played by HIFs in cancer, and the ongoing efforts to develop therapeutic agents against this target.

缺氧诱导转录因子:肿瘤发生的设计师和抗癌药物发现的目标。
缺氧诱导因子(HIFs)作为肿瘤存活和生长的主调控因子发挥着举足轻重的作用,在缺氧压力下控制着一系列细胞过程。临床数据表明,HIF-1 和 HIF-2 水平的上调与侵袭性肿瘤表型和患者预后不良有关。尽管 HIFs 作为癌症靶点已得到广泛验证,但药物靶向 HIFs,特别是形成活性转录因子的 α 和 β 亚基之间的相互作用,仍具有挑战性。尽管如此,许多针对这一途径不同部分的 HIFs 间接抑制剂已被发现。在开发 HIF-2 直接抑制剂方面也取得了重大进展,例如美国食品及药物管理局批准贝珠替凡用于治疗转移性透明细胞肾癌。虽然利用各种治疗方法靶向 HIF-1 的努力已显示出前景,但尚未出现临床候选药物。本综述旨在深入探讨 HIFs 在癌症中发挥的复杂而广泛的作用,以及目前针对这一靶点开发治疗药物的努力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Transcription-Austin
Transcription-Austin BIOCHEMISTRY & MOLECULAR BIOLOGY-
CiteScore
6.50
自引率
5.60%
发文量
9
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