Abstract
Interaction of the urokinase receptor (uPAR) with its binding partners such as the urokinase-type plasminogen activator (uPA) at the cell surface triggers a series of proteolytic and signaling events that promote invasion and metastasis. Here, we report the discovery of a small molecule (IPR-456) and its derivatives that inhibit the tight uPAR•uPA protein-protein interaction. IPR-456 was discovered by virtual screening against multiple conformations of uPAR sampled from explicit-solvent molecular dynamics simulations. Biochemical characterization reveal that the compound binds to uPAR with submicromolar affinity (K d = 310 nM) and inhibits the tight protein-protein interaction with an IC 50 of 10 μM. Free energy calculations based on explicit-solvent molecular dynamics simulations suggested the importance of a carboxylate moiety on IPR-456, which was confirmed by the activity of several derivatives including IPR-803. Immunofluorescence imaging showed that IPR-456 inhibited uPA binding to uPAR of breast MDA-MB-231 tumor cells with an IC 50 of 8 μM. The compounds blocked MDA-MB-231 cell invasion, but IPR-456 showed little effect on MDA-MB-231 migration and no effect on adhesion, suggesting that uPAR mediates these processes through its other binding partners.
| Original language | English |
|---|---|
| Pages (from-to) | 1232-1243 |
| Number of pages | 12 |
| Journal | ACS Chemical Biology |
| Volume | 6 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 18 2011 |
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ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
Cite this
Targeting multiple conformations leads to small molecule inhibitors of the uPAR•uPA protein-protein interaction that block cancer cell invasion. / Khanna, May; Wang, Fang; Jo, Inha; Knabe, W. Eric; Wilson, Sarah M.; Li, Liwei; Bum-Erdene, Khuchtumur; Li, Jing; W. Sledge, George; Khanna, Rajesh; Meroueh, Samy.
In: ACS Chemical Biology, Vol. 6, No. 11, 18.11.2011, p. 1232-1243.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Targeting multiple conformations leads to small molecule inhibitors of the uPAR•uPA protein-protein interaction that block cancer cell invasion
AU - Khanna, May
AU - Wang, Fang
AU - Jo, Inha
AU - Knabe, W. Eric
AU - Wilson, Sarah M.
AU - Li, Liwei
AU - Bum-Erdene, Khuchtumur
AU - Li, Jing
AU - W. Sledge, George
AU - Khanna, Rajesh
AU - Meroueh, Samy
PY - 2011/11/18
Y1 - 2011/11/18
N2 - Interaction of the urokinase receptor (uPAR) with its binding partners such as the urokinase-type plasminogen activator (uPA) at the cell surface triggers a series of proteolytic and signaling events that promote invasion and metastasis. Here, we report the discovery of a small molecule (IPR-456) and its derivatives that inhibit the tight uPAR•uPA protein-protein interaction. IPR-456 was discovered by virtual screening against multiple conformations of uPAR sampled from explicit-solvent molecular dynamics simulations. Biochemical characterization reveal that the compound binds to uPAR with submicromolar affinity (K d = 310 nM) and inhibits the tight protein-protein interaction with an IC 50 of 10 μM. Free energy calculations based on explicit-solvent molecular dynamics simulations suggested the importance of a carboxylate moiety on IPR-456, which was confirmed by the activity of several derivatives including IPR-803. Immunofluorescence imaging showed that IPR-456 inhibited uPA binding to uPAR of breast MDA-MB-231 tumor cells with an IC 50 of 8 μM. The compounds blocked MDA-MB-231 cell invasion, but IPR-456 showed little effect on MDA-MB-231 migration and no effect on adhesion, suggesting that uPAR mediates these processes through its other binding partners.
AB - Interaction of the urokinase receptor (uPAR) with its binding partners such as the urokinase-type plasminogen activator (uPA) at the cell surface triggers a series of proteolytic and signaling events that promote invasion and metastasis. Here, we report the discovery of a small molecule (IPR-456) and its derivatives that inhibit the tight uPAR•uPA protein-protein interaction. IPR-456 was discovered by virtual screening against multiple conformations of uPAR sampled from explicit-solvent molecular dynamics simulations. Biochemical characterization reveal that the compound binds to uPAR with submicromolar affinity (K d = 310 nM) and inhibits the tight protein-protein interaction with an IC 50 of 10 μM. Free energy calculations based on explicit-solvent molecular dynamics simulations suggested the importance of a carboxylate moiety on IPR-456, which was confirmed by the activity of several derivatives including IPR-803. Immunofluorescence imaging showed that IPR-456 inhibited uPA binding to uPAR of breast MDA-MB-231 tumor cells with an IC 50 of 8 μM. The compounds blocked MDA-MB-231 cell invasion, but IPR-456 showed little effect on MDA-MB-231 migration and no effect on adhesion, suggesting that uPAR mediates these processes through its other binding partners.
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UR - http://www.scopus.com/inward/citedby.url?scp=81555208984&partnerID=8YFLogxK
U2 - 10.1021/cb200180m
DO - 10.1021/cb200180m
M3 - Article
C2 - 21875078
AN - SCOPUS:81555208984
VL - 6
SP - 1232
EP - 1243
JO - ACS Chemical Biology
JF - ACS Chemical Biology
SN - 1554-8929
IS - 11
ER -