PMID- 27386732
OWN - NLM
STAT- MEDLINE
DCOM- 20170619
LR  - 20171218
IS  - 1520-4812 (Electronic)
IS  - 1043-1802 (Linking)
VI  - 27
IP  - 8
DP  - 2016 Aug 17
TI  - Identification of Targets of the HIF-1 Inhibitor IDF-11774 Using 
      Alkyne-Conjugated Photoaffinity Probes.
PG  - 1911-20
LID - 10.1021/acs.bioconjchem.6b00305 [doi]
AB  - 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-1alpha refolding and stimulates HIF-1alpha 
      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-1alpha degradation in cancer cells.
FAU - Ban, Hyun Seung
AU  - Ban HS
FAU - Naik, Ravi
AU  - Naik R
AD  - College of Pharmacy, Dongguk University-Seoul , Goyang 410-820, Korea.
FAU - Kim, Hwan Mook
AU  - Kim HM
AD  - Gachon University , College of Pharmacy, Incheon 406-840, Korea.
FAU - Kim, Bo-Kyung
AU  - Kim BK
FAU - Lee, Hongsub
AU  - Lee H
AD  - ILDONG Pharmaceutical Co. Ltd. , Hwaseong, Kyungi-do 445-811, Korea.
FAU - Kim, Inhyub
AU  - Kim I
FAU - Ahn, Heechul
AU  - Ahn H
AD  - College of Pharmacy, Dongguk University-Seoul , Goyang 410-820, Korea.
FAU - Jang, Yerin
AU  - Jang Y
AD  - College of Pharmacy, Dongguk University-Seoul , Goyang 410-820, Korea.
FAU - Jang, Kyusik
AU  - Jang K
AD  - College of Pharmacy, Dongguk University-Seoul , Goyang 410-820, Korea.
FAU - Eo, Yumi
AU  - Eo Y
AD  - College of Pharmacy, Dongguk University-Seoul , Goyang 410-820, Korea.
FAU - Song, Kyung Bin
AU  - Song KB
AD  - Department of Food Science and Technology, Chungnam National University , Daejeon 
      305-764, Korea.
FAU - Lee, Kyeong
AU  - Lee K
AD  - College of Pharmacy, Dongguk University-Seoul , Goyang 410-820, Korea.
FAU - Won, Misun
AU  - Won M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160718
PL  - United States
TA  - Bioconjug Chem
JT  - Bioconjugate chemistry
JID - 9010319
RN  - 0 (Alkynes)
RN  - 0 (HSP70 Heat-Shock Proteins)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (IDF-11774)
RN  - 0 (Piperazines)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - 8SKN0B0MIM (Benzoic Acid)
RN  - PJY633525U (Adamantane)
SB  - IM
MH  - Adamantane/*analogs & derivatives/pharmacology
MH  - Adenosine Triphosphate/biosynthesis
MH  - Alkynes/*chemistry
MH  - Allosteric Site/drug effects
MH  - Benzoic Acid/*pharmacology
MH  - Cell Respiration/drug effects
MH  - HCT116 Cells
MH  - HSP70 Heat-Shock Proteins/*antagonists & inhibitors/*chemistry/metabolism
MH  - Humans
MH  - Hypoxia-Inducible Factor 1/*antagonists & inhibitors
MH  - Mitochondria/drug effects/metabolism
MH  - Models, Molecular
MH  - Piperazines/*pharmacology
MH  - Protein Conformation
MH  - Protein Domains
MH  - Staining and Labeling
EDAT- 2016/07/09 06:00
MHDA- 2017/06/20 06:00
CRDT- 2016/07/09 06:00
PHST- 2016/07/09 06:00 [entrez]
PHST- 2016/07/09 06:00 [pubmed]
PHST- 2017/06/20 06:00 [medline]
AID - 10.1021/acs.bioconjchem.6b00305 [doi]
PST - ppublish
SO  - Bioconjug Chem. 2016 Aug 17;27(8):1911-20. doi: 10.1021/acs.bioconjchem.6b00305. 
      Epub 2016 Jul 18.