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Progress in Chemistry 2021, Vol. 33 Issue (12): 2259-2269 DOI: 10.7536/PC201141 Previous Articles   Next Articles

• Review •

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: Revised: Online: Published:
  • Contact: Shengnan Liu, Qingzhi Gao
  • Supported by:
    the National Natural Science Foundation of China(21772144); the National Key R&D Program of China(2020YFA0907903)
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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
Fig.1 Structure of HIF-1
Fig.2 Oxygen independent regulation pathway of HIF-1
Fig.3 Inhibitor EZN-2968 that decreases HIF-1α mRNA expression
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
Fig.4 Inhibitors that decrease HIF-1α protein expression
Fig.5 Compounds that increase HIF-1α protein degradation
Fig.6 Inhibitors of HIF-1α/HIF-1β dimerization and/or HIF-1-DNA binding
Fig.7 Inhibitors that decrease HIF-1 transcriptional activity
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