Targeting multiple conformations leads to small molecule inhibitors of the uPAR•uPA protein-protein interaction that block cancer cell invasion

May Khanna, Fang Wang, Inha Jo, W. Eric Knabe, Sarah M. Wilson, Liwei Li, Khuchtumur Bum-Erdene, Jing Li, George W. Sledge, Rajesh Khanna, Samy Meroueh

Research output: Contribution to journalArticle

36 Citations (Scopus)

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 languageEnglish
Pages (from-to)1232-1243
Number of pages12
JournalACS Chemical Biology
Volume6
Issue number11
DOIs
StatePublished - Nov 18 2011

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Conformations
Cells
Urokinase-Type Plasminogen Activator
Molecules
Molecular Dynamics Simulation
Neoplasms
Proteins
Molecular dynamics
Derivatives
Computer simulation
Free energy
Fluorescent Antibody Technique
Tumors
Screening
Breast
Adhesion
2-((3-(3,5-dimethylpiperidin-1-yl)-6-oxo-6H-anthra(1,9-cd)isoxazol-5-yl)amino)benzoic acid
Neoplasm Metastasis
Imaging techniques

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 journalArticle

Khanna, M, Wang, F, Jo, I, Knabe, WE, Wilson, SM, Li, L, Bum-Erdene, K, Li, J, W. Sledge, G, Khanna, R & Meroueh, S 2011, 'Targeting multiple conformations leads to small molecule inhibitors of the uPAR•uPA protein-protein interaction that block cancer cell invasion', ACS Chemical Biology, vol. 6, no. 11, pp. 1232-1243. https://doi.org/10.1021/cb200180m
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. / Targeting multiple conformations leads to small molecule inhibitors of the uPAR•uPA protein-protein interaction that block cancer cell invasion. In: ACS Chemical Biology. 2011 ; Vol. 6, No. 11. pp. 1232-1243.
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