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化学进展 2021, Vol. 33 Issue (12): 2259-2269 DOI: 10.7536/PC201141 前一篇   后一篇

• 综述 •

抗肿瘤缺氧诱导因子-1的小分子抑制剂

王欣瑜1, 赵富平1, 张儒1, 孙子茹1, 刘胜男1,2,*(), 高清志1,*()   

  1. 1 天津大学药物科学与技术学院 天津市现代药物传递及功能高效化重点实验室 天津 300072
    2 天津大学分子+研究院 天津 300072
  • 收稿日期:2020-12-09 修回日期:2021-03-08 出版日期:2021-12-20 发布日期:2021-07-29
  • 通讯作者: 刘胜男, 高清志
  • 基金资助:
    国家自然科学基金项目(21772144); 国家重点研发计划(2020YFA0907903)
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Development of Hypoxia Inducible Factor-1 Small Molecule Inhibitors as Antitumor Agents

Xinyu Wang1, Fuping Zhao1, Ru Zhang1, Ziru Sun1, Shengnan Liu1,2(), Qingzhi Gao1()   

  1. 1 School of Pharmaceutical Science and Technology, Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, Tianjin University,Tianjin 300072, China
    2 Institute of Molecular Plus, Tianjin University,Tianjin 300072, China
  • Received:2020-12-09 Revised:2021-03-08 Online:2021-12-20 Published:2021-07-29
  • Contact: Shengnan Liu, Qingzhi Gao
  • Supported by:
    the National Natural Science Foundation of China(21772144); the National Key R&D Program of China(2020YFA0907903)

肿瘤的缺氧微环境与其增殖、分化、血管生成、能量代谢、耐药性的发生以及患者预后状况密切相关。缺氧诱导因子1(Hypoxia-inducible factor 1, HIF-1)是细胞适应缺氧环境的重要转录因子和调控蛋白,通过调控下游靶基因如EPO、VEGF、GLUT等的表达,促进血管新生及有氧糖酵解以适应缺氧的环境,进而影响肿瘤细胞代谢、血管生成和肿瘤转移等。因此,开发以HIF-1为靶标的小分子抑制剂药物有望成为一种有效的肿瘤治疗方法。本文就HIF-1小分子抑制剂在肿瘤学研究中的进展进行综述,旨在为靶向HIF-1抗肿瘤药物的研发提供新思路。

关键词： HIF-1, HIF-1α, 信号通路, 小分子抑制剂, 抗肿瘤治疗

Tumor hypoxia is associated with tumor proliferation, differentiation, angiogenesis and energy metabolism. It has been found that hypoxia induces chemoresistance and poor prognosis in varieties of solid tumors. Hypoxia-inducible factor 1 (HIF-1) is an important transcription factor and regulator for inducing cells to adapt to hypoxia or anoxia environment. By regulating the expression of downstream targets such as EPO, VEGF, and GLUT, HIF-1 has been implicated in the activation of tumor glycolysis, angiogenesis and metastasis. Therefore, the discovery and development of small molecule inhibitors targeting HIF-1 may potentially lead to new chemotherapy for cancer treatment. In this review, we summarize the current state of the art and recent progress in the development of HIF-1 small molecule inhibitors, which may provide new insights into the design and discovery of HIF-1 targeted innovational drugs.

Contents

1 Introduction

2 Tumor hypoxia-inducible factor signaling pathway

2.1 Oxygen dependent regulation of HIF-1

2.2 Oxygen independent regulation of HIF-1

3 Antitumor small molecule inhibitors targeting HIF-1

3.1 Decreased HIF-1α mRNA expression

3.2 Decreased HIF-1α protein expression

3.3 Increased HIF-1α protein degradation

3.4 Decreased HIF heterodimerization

3.5 Decreased HIF DNA binding

3.6 Decreased HIF-1 transcriptional activity

4 Outlook

Key words: HIF-1, HIF-1α, signaling pathway, small molecule inhibitors, anti-tumor therapy
()
图1 HIF-1的结构
Fig.1 Structure of HIF-1
图2 HIF-1的非氧依赖调节途径
Fig.2 Oxygen independent regulation pathway of HIF-1
图3 降低HIF-1α mRNA表达水平的抑制剂EZN-2968
Fig.3 Inhibitor EZN-2968 that decreases HIF-1α mRNA expression
表1 HIF-1抑制剂在癌症中的临床试验研究
Table 1 Clinical trials of HIF-1 inhibitors in several cancers
Compound name Diseases Trial stage Status
Acriflavine - - -
Apigenin Colorectal cancer Phase Ⅱ Suspended
Bay 87-2243 Neoplasms Phase I Terminated
Bisphenol A Breast cancer Unkown Completed
Daunorubicin Acute myeloid leukemia Phase Ⅱ Completed
Doxorubicin Advanced solid tumours Phase I Completed
Echinomycin - - -
ENMD-1198 - - -
ETP (±)-3 - - -
EZN-2968 Neoplasms, liver metastases Phase I Completed
Indenopyrazole 2l - - -
LXY 6006 - - -
LXY 6090 - - -
Manassantin A - - -
NNC 55-0396 - - -
PS-341 Prostate neoplasms Phase Ⅱ Completed
PX-478 Advanced solid tumors, lymphoma Phase I Completed
Quinazolin-4-one 1 - - -
Remodelin - - -
YC-1 - - -
2ME2 Unspecified adult solid tumor Phase I Completed
图4 降低HIF-1α蛋白表达水平的抑制剂
Fig.4 Inhibitors that decrease HIF-1α protein expression
图5 促进HIF-1α蛋白降解的化合物
Fig.5 Compounds that increase HIF-1α protein degradation
图6 HIF-1α/HIF-1β二聚化及HIF-1与DNA结合的抑制剂
Fig.6 Inhibitors of HIF-1α/HIF-1β dimerization and/or HIF-1-DNA binding
图7 HIF-1转录活性抑制剂
Fig.7 Inhibitors that decrease HIF-1 transcriptional activity
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