- Probe for detecting HSP70 and manufacturing method thereof
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The present invention relates to a probe for detecting heat shock protein (HSP) 70 as a target protein of IDF-11774, a compound capable of inhibiting activities of hypoxia inducible factor-1 (HIF-1). The present invention further relates to a production method thereof. By using the probe of the present invention, it is possible to know that the IDF-11774 binds to an allosteric site of HSP70 and inhibits chaperone activities of HSP70 by reducing refolding, thereby inhibiting activities of HIF-1. The probe can also be used to develop drugs to suppress proliferation and metastasis of cancer in an investigation on the target protein of IDF-11774.(AA) Probe 1: R=H(BB) Probe 2: R=Adamantyl(CC) Probe 3: R=H(DD) Probe 4: R=AdamantylCOPYRIGHT KIPO 2018
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Paragraph 0157; 0163-0164
(2018/05/03)
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- Identification of Targets of the HIF-1 Inhibitor IDF-11774 Using Alkyne-Conjugated Photoaffinity Probes
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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.
- Ban, Hyun Seung,Naik, Ravi,Kim, Hwan Mook,Kim, Bo-Kyung,Lee, Hongsub,Kim, Inhyub,Ahn, Heechul,Jang, Yerin,Jang, Kyusik,Eo, Yumi,Song, Kyung Bin,Lee, Kyeong,Won, Misun
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p. 1911 - 1920
(2016/09/04)
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