This technology includes newly identified best-in-class inhibitors of the p53-S100B interaction that plays a role in malignant melanoma. S100B contributes to cancer cell proliferation (particularly malignant melanoma) by binding to p53 and inhibiting its tumor suppressor function. A high-throughput screen was used to find p53-S100B inhibitors, leading to the identification of a putative inhibitor, which was then subjected to medicinal chemistry optimization. Structure-based design was then used to develop compounds with significantly improved potency.