Abstract 4524: A rational approach for the discovery of inhibitors of NSD2 for the treatment of multiple myeloma

Multiple myeloma (MM) is a plasma cell malignancy which accounts for approximately 10% of hematologic malignancies. Despite the introduction of new therapeutic agents, MM remains incurable and nearly all patients ultimately relapse. About 20% of MM are due to a chromosomal translocation t(4;14) leading to overexpression of the NSD2 histone methyltransferase. NSD2 catalyzes dimethylation of lysine 36 on histone H3 (H3K36me2) and is associated with transcriptionally active regions. Several studies have shown that in MM harboring the translocation t(4;14), oncogenic programming is dependent on the methyltransferase activity of NSD2. Thus, NSD2 inhibitors are potential therapeutics for this devastating cancer Using the AlphaLisa™ technology, we screened 240,000 compounds coming from our proprietary library. The assay was based on the detection of H3K36me2 on nucleosome by a specific antibody. False positives hits were removed by a technological counterscreen, and compounds with redox or metal contamination activity were excluded. For confirmation purposes, an orthogonal counter-screen based on 3H SAM incorporation was performed. The IC 50 obtained for one of the best compounds across the AlphaLisa and 3H SAM incorporation are very similar, showing values of 0.15 μM and 0.29 μM respectively for compound 1. Binding affinities measured by MST and SPR for compound 1 were consistent with the IC 50 observed in the biochemical assays K D = 0.19 μM for MST and 1.7 μM by SPR. This compound was also shown to be a good binder by NMR (STD), and further experiments are planned to elucidate the selectivity and MOA of this series. To our knowledge, no NSD2 inhibitor have been identified to date despite several screening efforts performed by other groups. We believe that our hits are promising starting points to generate potent and selective NSD2 inhibitors. Citation Format: Claudia Fromond, Xavier Espanel, Severine Estevez, Vanessa Adarbes, Stephanie Bocart, Bruno Loillier, Anne Soude, Nathalie Urban, Frederic Bell, Philippe Masson, Benaissa Boubia, Pierre Broqua, Christian Montalbetti. A rational approach for the discovery of inhibitors of NSD2 for the treatment of multiple myeloma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4524.