Design and Synthesis of Novel Small-Molecule Inhibitors of the Hypoxia Inducible Factor Pathway
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- 作者：Suazette Reid Mooring ; Hui Jin ; Narra S. Devi ; Adnan A. Jabbar ; Stefan Kaluz ; Yuan Liu ; Erwin G. Van Meir ; Binghe Wang
- 刊名：Journal of Medicinal Chemistry
- 出版年：2011
- 出版时间：December 22, 2011
- 年：2011
- 卷：54
- 期：24
- 页码：8471-8489
- 全文大小：734K
- 年卷期：v.54,no.24(December 22, 2011)
- ISSN：1520-4804
文摘
Hypoxia, a reduction in partial oxygen pressure, is a salient property of solid tumors. Hypoxia drives malignant progression and metastasis in tumors and participates in tumor resistance to radio- and chemotherapies. Hypoxia activates the hypoxia-inducible factor (HIF) family of transcription factors, which induce target genes that regulate adaptive biological processes such as anaerobic metabolism, cell motility, and angiogenesis. Clinical evidence has demonstrated that expression of HIF-1 is strongly associated with poor patient prognosis and activation of HIF-1 contributes to malignant behavior and therapeutic resistance. Consequently, HIF-1 has become an important therapeutic target for inhibition by small molecules. Herein, we describe the design and synthesis of small molecules that inhibit the HIF-1 signaling pathway. Many of these compounds exhibit inhibitory activity in the nanomolar range. Separate mechanistic studies indicate that these inhibitors do not alter HIF-1 levels but interfere with the ability of HIF-1伪/HIF-1尾 to interact with cofactors p300/CBP to form an active transcriptional complex.