Abstract 1127: MMSET: Can we flip the switch.
Authors: Christine Will, Michael Scholle, Roodolph St. Pierre, Ji Hyun Shim, Zhong Jun Cheng, Relja Popovic, Dinshaw J. Patel, James E. Bradner, Alex D. MacKerell, Milan Mrksich, Jonathan D. Licht
Journal: Cancer Research (2013)

Abstract Epigenetic regulation of gene expression involves covalent modifications of histones and DNA in a way that does not alter the underlying DNA sequence. Recently, misregulation of epigenetic mechanisms has been linked to a number of diseases, including cancer. These data signify the importance of understanding normal and aberrant epigenetic regulation and for development of tools that allow us to modulate various aspects of epigenetic machinery. One approach to do this is by targeting epigenetic enzymes with small molecule inhibitors. MMSET (Multiple Myeloma SET domain), is a histone methyltransferase overexpressed in many cancers, including a subset of multiple myelomas (MM) harboring the t(4;14) translocation. Overexpression of MMSET leads to a global increase in dimethylation of lysine 36 on histone H3 (H3K36me2). The ability of MMSET to methylate H3 depends on a functional SET (Suppressor of variegation, Enhancer of zeste and Trithorax) domain, found in most histone methyltransferases. Methylation of H3K36 by MMSET affects overall chromatin structure thereby affecting the expression of many genes, including genes that play a role in cellular proliferation and adhesion. Conversely, the loss of MMSET in t(4;14)+ cells suppresses cell growth and induces apoptosis thus supporting the idea that inhibition of MMSET activity is a viable approach to treatment of this particular type of myeloma. Currently there are not any known inhibitors of MMSET. Using the previously identified structure of the SET domain of NSD1, an MMSET homologue, we performed an in silico screen against a library of compounds to identify those that may fit in the substrate binding pocket of MMSET. We tested the in silico hits in a high throughput screen (HTS) that combines Self-Assembled Monolayers and matrix-assisted laser Desorption Ionization time-of-flight (SAMDI). This method allows us to test the ability of the compounds to inhibit MMSET's methylation activity in a label-free format. From this screen two potential hits have been identified. These compounds have IC50 values in the micromolar range and Differential Scanning Fluorimetry (DSF) confirmed the binding of the small molecule to MMSET. Future in vivo work will determine the potency and selectivity of these compounds towards MMSET. Identifying an effective inhibitor of MMSET could make way for new potential therapeutics in the treatment of t(4;14)+ multiple myeloma, as well as other cancers that overexpress this protein, and could also prove to be highly useful in our efforts to understand the various mechanisms of epigenetic regulation. Citation Format: Christine Will, Michael Scholle, Roodolph St. Pierre, Ji Hyun Shim, Zhong Jun Cheng, Relja Popovic, Dinshaw J. Patel, James E. Bradner, Alex D. MacKerell, Milan Mrksich, Jonathan D. Licht. MMSET: Can we flip the switch. [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 1127. doi:10.1158/1538-7445.AM2013-1127