Background: Integrins provide potentially useful targets at which to direct intervention therapy to halt cancer progression.One integrin, called alpha V beta 6, is restricted to epithelial cells and has been implicated in tumour growth.Aberrant activation of the ERK mitogen-activated protein kinase pathway has also been shown to be a feature of many human cancers.We have previously reported that the cytoplasmic tail of the beta 6 integrin subunit binds directly to the kinase ERK2 and that deletion of the ERK2-binding domain from the cytoplasmic tail of beta 6 suppresses tumour growth (Ahmed et al, Oncogene 21:1370; 2002).Aim: To examine the ability of synthetic peptides based on the beta 6-ERK2 binding domain to inhibit cancer cell proliferation in vitro.Methods: HT29 (colon), DU145 (prostate) and MCF-7 (breast) cancer cell lines were obtained from the American Type Culture Collection.In vitro cell proliferation was assessed using the MTT assay.Activated phosphor-ERK and apoptosis was determined in cell-based systems using commercially available ELISA kits (pERK and Caspase 3 kits from Australian Biosearch).In vivo toxicity was determined in Balb/c nude mice.Results: Growth experiments performed with a deletion mutant of the 15 mer ERK2 binding domain of the beta 6 integrin subunit revealed enhanced inhibition of colon cancer cell proliferation by a 10 mer peptide compared with the 15-mer peptide fragment.Chemical modification of the 10 mer peptide (designated 1K248) yielded a compound that inhibited proliferation of different cancer cell types, induced apoptosis, inhibited ERK activity in a cell-based assay and was non-toxic upon repeated intravenous administration to nude mice at a dose of 20 mgs/kg.Conclusion: INTER-K Ptys novel suite of compounds based upon integrin-ERK binding domains are highly soluble and stable in physiological solvents.1K248 and related homologs derived from other beta integrin subunits may serve as anti-cancer drugs when used either alone or in combination with standard chemotherapy.