Abstract
IHY-153 (2-(2,5-difluorobenzyl)-3,4-dihydro-5-(10-hydroxydecyl)-6- methoxy-1-undecylisoquinolinium bromide) was recently discovered as a small molecule that potently inhibits proliferation of tumor cells by inducing cell-cycle arrest at G0-G1 phase. To investigate the basis of anti-proliferative activity of IHY-153, cellular binding proteins of biotinyl-IHY-153 were screened using T7 phage displayed human cDNA libraries. Calmodulin-expressing phage specifically bound to immobilized IHY-153 in a Ca2+-dependent manner. The interaction between IHY-153 and Ca2+//CaM was validated through phage competition binding assays, surface plasmon resonance analysis, and molecular modeling. IHY-153 induced sustained phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and subsequently increased p21WAF1 expression in colon cancer cells. These results demonstrate that IHY-153, a novel small molecule, targets Ca2+/CaM and indicate that this compound functions as an anti-proliferative agent by influencing Ca2+/CaM- dependent signal transduction.
| Original language | English |
|---|---|
| Pages (from-to) | 423-432 |
| Number of pages | 10 |
| Journal | Proteomics - Clinical Applications |
| Volume | 3 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 2009 May 14 |
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All Science Journal Classification (ASJC) codes
- Clinical Biochemistry
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Identification and validation of calmodulin as a binding protein of an anti-proliferative small molecule 3,4-dihydroisoquinolinium salt. / Jung, Hye Jin; Shim, Joong Sup; Park, Jungchan; Ha, Hyun Joon; Kim, Jung Ho; Kim, Joong Gon; Kim, Nam Doo; Yoon, Jeong Hyeok; Kwon, Ho Jeong.
In: Proteomics - Clinical Applications, Vol. 3, No. 4, 14.05.2009, p. 423-432.Research output: Contribution to journal › Article
TY - JOUR
T1 - Identification and validation of calmodulin as a binding protein of an anti-proliferative small molecule 3,4-dihydroisoquinolinium salt
AU - Jung, Hye Jin
AU - Shim, Joong Sup
AU - Park, Jungchan
AU - Ha, Hyun Joon
AU - Kim, Jung Ho
AU - Kim, Joong Gon
AU - Kim, Nam Doo
AU - Yoon, Jeong Hyeok
AU - Kwon, Ho Jeong
PY - 2009/5/14
Y1 - 2009/5/14
N2 - IHY-153 (2-(2,5-difluorobenzyl)-3,4-dihydro-5-(10-hydroxydecyl)-6- methoxy-1-undecylisoquinolinium bromide) was recently discovered as a small molecule that potently inhibits proliferation of tumor cells by inducing cell-cycle arrest at G0-G1 phase. To investigate the basis of anti-proliferative activity of IHY-153, cellular binding proteins of biotinyl-IHY-153 were screened using T7 phage displayed human cDNA libraries. Calmodulin-expressing phage specifically bound to immobilized IHY-153 in a Ca2+-dependent manner. The interaction between IHY-153 and Ca2+//CaM was validated through phage competition binding assays, surface plasmon resonance analysis, and molecular modeling. IHY-153 induced sustained phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and subsequently increased p21WAF1 expression in colon cancer cells. These results demonstrate that IHY-153, a novel small molecule, targets Ca2+/CaM and indicate that this compound functions as an anti-proliferative agent by influencing Ca2+/CaM- dependent signal transduction.
AB - IHY-153 (2-(2,5-difluorobenzyl)-3,4-dihydro-5-(10-hydroxydecyl)-6- methoxy-1-undecylisoquinolinium bromide) was recently discovered as a small molecule that potently inhibits proliferation of tumor cells by inducing cell-cycle arrest at G0-G1 phase. To investigate the basis of anti-proliferative activity of IHY-153, cellular binding proteins of biotinyl-IHY-153 were screened using T7 phage displayed human cDNA libraries. Calmodulin-expressing phage specifically bound to immobilized IHY-153 in a Ca2+-dependent manner. The interaction between IHY-153 and Ca2+//CaM was validated through phage competition binding assays, surface plasmon resonance analysis, and molecular modeling. IHY-153 induced sustained phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and subsequently increased p21WAF1 expression in colon cancer cells. These results demonstrate that IHY-153, a novel small molecule, targets Ca2+/CaM and indicate that this compound functions as an anti-proliferative agent by influencing Ca2+/CaM- dependent signal transduction.
UR - http://www.scopus.com/inward/record.url?scp=65549109049&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=65549109049&partnerID=8YFLogxK
U2 - 10.1002/prca.200800060
DO - 10.1002/prca.200800060
M3 - Article
C2 - 21136969
AN - SCOPUS:65549109049
VL - 3
SP - 423
EP - 432
JO - Proteomics - Clinical Applications
JF - Proteomics - Clinical Applications
SN - 1862-8346
IS - 4
ER -