Abstract 2226: Structure/function characterization of SBi4225, a novel inhibitor of the calcium-binding protein S100B.

Abstract

Abstract The S100 family of proteins displays no enzymatic activity but has been shown to play roles in an array of biological functions such as calcium homeostasis, cellular growth, inflammation, and metabolism. The influence of these homodimeric proteins is mediated through protein-protein interactions in a typically calcium dependent manner and aberrant expression of S100 proteins has been linked to a variety of cancers, cardiomyopathies, and neurological disorders. Of particular interest, S100B is highly over-expressed in many cancers, including malignant melanoma (MM). In MM, S100B is used as prognostic indicator in evaluating treatment success and in predicting relapse. Studies now show that S100B is more than a clinical marker, and that it binds wild-type p53 in a calcium-dependent manner, sequestering it, and promoting its degradation. This results in the loss of p53-dependent tumor suppression activities. As inhibition of S100B expression by RNA interference restores both wild-type p53 protein levels and normal transcriptional activation/apoptosis activities, we have made it our long-term goal is to specifically inhibit the S100B-p53 interaction in order to restore the p53 tumor suppression function as a potential therapy for malignant melanoma. Although we have succeeded in identifying many S100B inhibitors (also known as SBiXs), optimization studies are a necessary part of the development of drugs with useful therapeutic activities. Included amongst these optimization studies are characterizations of structure-activity relationships (SAR). Our initial SAR studies have resulted in the development of a second series of SBiXs. Amongst this series is the novel S100B inhibitor, SBi4225. As part of the cyclical process of SAR studies, the binding of SBi4225 to S100B has been investigated using X-ray crystallography. As described within, SBi4225 binds to S100B in a position and orientation analogous to its predecessors, SBi4211 and SBi1. NMR data including chemical shift perturbations of 15N isotopically labeled protein backbone were consistent with the X-ray crystal structures and demonstrated the relevance of the SBi4225-S100B complex in solution. This new understanding of the SBi4225 structure/function relationship will undoubtedly impact the development and optimization of future SBiXs. Citation Format: Michael C. Cavalier, Laura McKnight, David Weber, Paul Wilder. Structure/function characterization of SBi4225, a novel inhibitor of the calcium-binding protein S100B. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2226. doi:10.1158/1538-7445.AM2013-2226