Abstract
Abstract Summary: The calcium binding protein, S100B, has been directly linked to malignant melanoma (MM) and has long been used as a prognostic indicator. Studies have proven S100B to not only be a clinical marker within MM, but that it binds to the tumor suppressor p53, and promotes its degradation. p53 is typically found as wild-type in MM, and inhibition of S100B expression restores both p53 protein levels and normal transcriptional activation/apoptosis activities. Subsequently, we have made it our long-term goal to discover S100B inhibitors (SBiXs) in order to restore the p53 tumor suppression function in patients with MM, and have already identified many SBiXs. Purpose: It is our purpose to discover/synthesize and/or to improve existing inhibitors of S100B to restore p53 activity in human malignant melanoma. Amongst these SBiXs are compounds which covalently modify S100B. The effects of covalent SBiXs on S100B in Malignant Melanoma are to be investigated. Results and conclusions: The development of S100B inhibitors (SBiXs) is ongoing at the University of Maryland Schools of Pharmacy and Medicine with the goal of improving affinity and specificity towards inhibiting S100B. Fluorescent Polarization Completion Assays have identified compounds that bind S100B and inhibit melanoma cell growth. S100B binding by these SBiXs was confirmed using NMR spectroscopy. The crystallographic structures of the SBiX:S100B complexes were solved revealing covalent modifiers occupying persistent binding site 2. The compounds offer potential bridging scaffolds between sites 1 and 3. All five SBiXs demonstrated the ability to kill malignant melanoma with some killing in a S100B dependent manner. TheS100B-SBiX complexes presented will act as the basis for the design of improved SBiXs. SBiXs may also have therapeutic value for treating other cancers with elevated S100B and wt p53 such as astrocytoma, renal tumors, and some forms of leukemia. Citation Format: Michael C. Cavalier. Covalent inhibitors of S100B (SBiXs) in malignant melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3221. doi:10.1158/1538-7445.AM2014-3221
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