Monoclonal antibodies specific for the p185 HER2/neu growth factor receptor represent a significant advance in receptor-based therapy for p185 HER2/neu-expressing human cancers. We have used a structure-based approach to develop a small (1.5 kDa) exocyclic anti-HER2/neu peptide mimic (AHNP) functionally similar to an anti-p185 HER2/neu monoclonal antibody, 4D5 (Herceptin). The AHNP mimetic specifically binds to p185 HER2/neu with high affinity (K D= 300 nM). This results in inhibition of proliferation of p185 HER2/neu-overexpressing tumor cells, and inhibition of colony formation in vitro and growth of p185 HER2/neu-expressing tumors in athymic mice. In addition, the mimetic sensitizes the tumor cells to apoptosis when used in conjunction with ionizing radiation or chemotherapeutic agents. A comparison of the molar quantities of the Herceptin antibody and the AHNP mimetic required for inhibiting cell growth and anchorage-independent growth showed generally similar activities. The structure-based derivation of the AHNP represents a novel strategy for the design of receptor-specific tumor therapies.