Abstract B103: Inhibitors of S100B (SBiXs) in malignant melanoma.

Abstract

Abstract Summary: In malignant melanoma (MM), elevated levels of the tumor marker, S100B, binds directly to wild-type (wt) p53, dissociates the p53 tetramer, and down-regulates p53-dependent tumor suppression functions; therefore, it is the goal to develop S100B inhibitors (SBiXs; X=compound number) to restore active p53 in this deadly cancer. As a proof of principle for a drug design project, inhibiting S100B with small interfering antisense RNA (siRNAS100B) and several SBiXs was shown to restore wild-type p53 levels and its downstream gene products, as necessary to induce cell growth arrest and apoptosis in malignant melanoma. Purpose: It is our purpose to discover/synthesize and/or to improve existing inhibitors of S100B to restore p53 activity in human malignant melanoma. Such compounds can then be examined for in vivo efficacy. Results and conclusions: Development of S100B inhibitors (SBiXs) is ongoing at the University of Maryland Schools of Pharmacy and Medicine with the goal of obtaining higher affinity and better specificity towards inhibiting S100B. Computer aided drug design (CADD) followed by synthesis and experimental assays (i.e. NMR, binding, and cellular assays) have identified compounds that bind S100B and inhibit melanoma cell growth. Available binding data, IC50 data, and 3D structures of S100B-SBiX complexes will be presented that 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 Information: Mol Cancer Ther 2013;12(11 Suppl):B103. Citation Format: Michael Cavalier, Paul T. Wilder, Andrew Coop, Alexander MacKerell, David J. Weber. Inhibitors of S100B (SBiXs) in malignant melanoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B103.