In Vivo Screening of S100B Inhibitors for Melanoma Therapy

Abstract

S100 proteins are markers for numerous cancers, and in many cases high S100 protein levels are a prognostic indicator for poor survival. One such case is S100B, which is overproduced in a very large percentage of malignant melanoma cases. Elevated S100B protein was more recently validated to have causative effects towards cancer progression via down-regulating the tumor suppressor protein, p53. Towards eliminating this problem in melanoma, targeting S100B with small molecule inhibitors was initiated. This work relies on numerous chemical biology technologies including structural biology, computer-aided drug design, compound screening, and medicinal chemistry approaches. Another important component of drug development is the ability to test compounds and various molecular scaffolds for their efficacy in vivo. This chapter briefly describes the development of S100B inhibitors, termed SBiXs, for melanoma therapy with a focus on the inclusion of in vivo screening at an early stage in the drug discovery process.

S100B-p53 disengagement by pentamidine promotes apoptosis and inhibits cellular migration via aquaporin-4 and metalloproteinase-2 inhibition in C6 glioma cells

“…By contrast, BAX protein is known to induce apoptosis in various cell lines (29). In concurrence with the antiproliferative activity of pentamidine described in a number of other cell types, including cultured human melanoma cells (16,17,30,31), the results of the present study indicate that pentamidine treatment dose-dependently increases the BAX/Bcl-2 ratio, demonstrating the pro-apoptotic role of this antiprotozoal agent in cultured glioma cells. The pro-apoptotic effect displayed by pentamidine appears to be directly associated with the inhibition of the S100B-p53 protein-protein interaction, resulting in a marked restoration of wild-type p53 protein function.…”

“…The pro-apoptotic effect displayed by pentamidine appears to be directly associated with the inhibition of the S100B-p53 protein-protein interaction, resulting in a marked restoration of wild-type p53 protein function. This effect is considered to be the pivotal mechanism of the anticancer effect of pentamidine (17,30,31). Among the various factors involved in the acquisition of invasive capacities by tumor cells, MMP-2 and AQP4 have emerged as critical markers of glioma cell migration.…”

Upregulation of S100P, receptor for advanced glycation end products and ezrin in malignant melanoma

“…Elevated S100B protein is known to downregulate p53 tumor suppressor protein, leading to cancer progression. Therefore, small‐molecule inhibitors targeting S100B–p53 interaction are under intense investigation as new therapeutic strategies for MM . Overproduction of S100A4 as well as S100A6 has also been reported in MM.…”

S100 proteins in cancer

“…These approaches have successfully identified new compounds that inhibit the interactions of S100P 149 , S100A4 (REFS 156,157), S100A9 (REF. 156), S100A10 (REF 158) and S100B 123,159 with their respective targets. An examination of these S100–small-molecule complexes has revealed that most small molecules target one of three distinct pockets within S100 proteins 160 (FIG.…”