Template Based Design of Anti-Metastatic Drugs from the Active Conformation of Laminin Peptide II
Abstract
Major advances were made towards elucidating the structure of the ligand-binding domain of the 67 kDa LBP. Phage display studies indicated that three sequence domains in the C-terminal domain of the LBP likely interact with peptide 11. Both GBl fusion domains and other cohesive domains of LBP, identified by limited proteolysis studies, have been expressed in recombinant bacterial systems. Well-dispersed NMR spectra have been generated for several of these, indicating that they will be useful for structure determination of the LBP ligand-binding domain. We now have a successful synthetic path for the candidate l6 YIGSR mimetic, which was designed by an early run of the INVENTON program. On receipt of sufficient material, this will shortly be investigated for its bioactivity. Structurally related compounds will be used in structure:activity studies to optimize the bioactivity of the mimetic. To facilitate the preclinical studies, metastatic variants of the MDA-MB-23l and MDA-MB-435 human breast cancer cell lines have been generated. Since we have found that LBP shedding is estrogen responsive, we have also derived more invasive variants of the T47D ER+ve breast cancer cell line. The LBP protein was shown to have a sulfhydryl oxidase activity, and facilitated peptide 11 dimerization.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2001
- Accession Number
- ADB265599
Entities
People
- Jean R. Starkey
Organizations
- Montana State University