Identification of targets of the HIF-1 inhibitor IDF-11774 using alkyne-conjugated photoaffinity probes = 광친화 화학 프로브를 이용한 IDF-11774의 타겟 확인

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Title
Identification of targets of the HIF-1 inhibitor IDF-11774 using alkyne-conjugated photoaffinity probes = 광친화 화학 프로브를 이용한 IDF-11774의 타겟 확인
Author(s)
Hyun Seung Ban; P Naik; H M Kim; Bo Kyung Kim; H Lee; Inhyub Kim; H Ahn; Y Jang; K Jang; Y Eo; K B Song; K Lee; Mi Sun Won
Bibliographic Citation
Bioconjugate Chemistry, vol. 27, no. 8, pp. 1911-1920
Publication Year
2016
Abstract
We developed a hypoxia-inducible factor-1 (HIF-1) inhibitor, IDF-11774, as a clinical candidate for cancer therapy. To understand the mechanism of action of IDF-11774, we attempted to isolate target proteins of IDF-11774 using bioconjugated probes. Multifunctional chemical probes containing sites for click conjugation and photoaffinity labeling were designed and synthesized. After fluorescence and photoaffinity labeling of proteins, two-dimensional electrophoresis (2DE) was performed to isolate specific molecular targets of IDF-11774. Heat shock protein (HSP) 70 was identified as a target protein of IDF-11774. We revealed that IDF-11774 inhibited HSP70 chaperone activity by binding to its allosteric pocket, rather than the ATP-binding site in its nucleotide-binding domain (NBD). Moreover, IDF-11774 reduced the oxygen consumption rate (OCR) and ATP production, thereby increasing intracellular oxygen tension. This result suggests that the inhibition of HSP70 chaperone activity by IDF-11774 suppresses HIF-1α refolding and stimulates HIF-1α degradation. Taken together, these findings indicate that IDF-11774-derived chemical probes successfully identified IDF-11774's target molecule, HSP70, and elucidated the mode of action of IDF-11774 in inhibiting HSP70 chaperone activity and stimulating HIF-1α degradation in cancer cells.
ISSN
1043-1802
Publisher
Amer Chem Soc
DOI
http://dx.doi.org/10.1021/acs.bioconjchem.6b00305
Type
Article
Appears in Collections:
Division of Biomedical Research > Biotherapeutics Translational Research Center > 1. Journal Articles
Division of Biomedical Research > Personalized Genomic Medicine Research Center > 1. Journal Articles
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