Signalling approaches to inhibition of cellular proliferation

There has been considerable progress in elucidating the mechanisms by which extracellular signals are transduced via cell surface receptors to trigger changes in gene expression determining the growth and differentiated state of the cell. Efforts to understand and target the mechanisms that underlie the development of abnormal proliferative diseases including vascular injury and cancer are under intense study [1,2]. We have targeted several strategies to inhibit cellular proliferation including blockade of platelet derived growth factor (PDGF) mediated mitogenic signalling and secondly with a downstream target by interfering with ras protein function via the enzyme ras farnesyl transferase (FTase) [1,2]. Strategies to develop potent cellular acting peptide inhibitors of the association of the C-terminal SH2 domain of the p85 subunit of phosphatidyl 3-kinase (PI, kinase) with the PDGF -receptor from the phosphorylated pentapeptide Tyr(PO3H2)751-Val-Pro-Met-Leu (IC50) = 0.67 pM) have led to potent tetraand tripeptide inhibitors. In the second signalling strategy, development of potent peptidomimetic inhibitors of the enzyme FTase are presented. Truncated triand dipeptides and peptidomimetics with cellular activity derived from the pentapeptide lead PD 083 176 (Cbz-His-Tyr(OBn)-Ser(OBn)-TrpDAla-NH2) (IC50)=17 nM) have been discovered.