Integrin alpha 6 (integrin α6β1 and integrin α6β4 ) 1 are important transmenbrane receptors whose dysfunction is always highly correlated with cancers2. CRWY peptide, an integrin alpha 6 targeting cyclic peptide was identified through phage display library, exhibited great value in cancer diagnosis and therapy. To overcome the drawback of proteolytic degradation of CRWY peptide in plasma and improve the target binding affinity, we conducted a comprehensive SAR and structural optimization study on CRWY peptide. The peptide sequence and conformation are two critical factors affecting peptide-target affinity and metabolic stability, thus we systematic modified the CRWY peptide with respect to the hot residues and optimal conformation exploration. We tried globally and locally restriction of the CRWY peptide as well as the cyclic linkage and investigated the key residues in parallel. Taken together, a redox-stable thioether linkage with the identification of binding motif of RWY led to an optimized lead peptide LPI 13 with good binding affinity better than CRWY peptide and good water solubility. LPI 13 served as a drug-like integrin alpha 6 targeting peptide candidate for further development as cancer diagnosis and peptide-drug conjugate therapeutics.