Abstract 1358: Structure-based drug design of 3-site binding, high affinity inhibitors of S100B in malignant melanoma

Abstract

Abstract An especially predictive biomarker when used in combination with other diagnostic indicators, S100B is elevated in >90% of malignant melanoma (MM) patients and its protein level correlates directly with poor survival (<1 yr.) and relapse. For patients with low levels of S100B (5-10%), MM vaccines are uniquely effective. While this correlation is not fully understood, mechanistic studies show that S100B is capable of blocking p53 oligomerization, promoting p53 phosphorylation in its C-terminus, and contributing to p53 degradation in concert with hdm2. Correspondingly, lowering S100B levels via siRNA or via small molecule inhibitors restore p53 levels and its tumor suppressor activities including UV-activated apoptosis pathways found in normal melanocytes. Additionally, elevated S100B and overexpression of the receptor for advanced glycation end products (RAGE) confers a metastatic phenotype. Studies into how S100B affects tumor progression and metastasis are ongoing, novel S100B inhibitors (termed SBiXs) to ablate S100B-dependent effects in cancer are in development. Structure-activity relationship (SAR) studies are ongoing to improve the affinity and selectivity of SBiXs. These studies reveal that the binding surface of S100B can be divided into “hot spots” or “persistent sites” that contribute more energetically to the protein-protein interactions (PPI) than the surrounding protein surface. Described here are descriptions of SBiXs which bind these Sites (1, 2, and 3), details to the SAR studies involved in the chemical optimization of these ligands, and information into the tethering of these SBiXs into a single-molecule capable of binding all 3 sites simultaneously. Also provided is a discussion regarding how protein dynamics affect the on/off rates of SBiXs and the resulting apparent binding affinity. The results described here represent a Structure-based drug design approach to the development of PPI inhibitors nearing the threshold required for a useful therapeutic window. Citation Format: Michael C. Cavalier, Paul T. Wilder, Diane Luci, David J. Maloney, Lei Fang, Mohd. Imran Ansari, Alexander D. MacKerell, Andrew Coop, Ajit Jadhav, David J. Weber. Structure-based drug design of 3-site binding, high affinity inhibitors of S100B in malignant melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1358.