Abstract A123: Structure-function studies and drug design on the histone lysine methyl methyltransferases NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L1.

Chromatin remodelers that include histone methyl transferases (HMTases) are becoming a focal point in cancer drug development. The NSD family of three HMTases, NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L are bona fide oncogenes found aberrantly expressed in several cancers, suggesting their potential role for novel therapeutic strategies. Several histone modifiers including HMTase have clear roles in human carcinogenesis but the extent of their functions and regulations are not well understood, especially in pathological conditions. The extents of the NSDs biological roles in normal and pathological conditions remain unclear. In particular, the substrate specificity of the NSDs remains unsettled and discrepant data has been reported. NSD2/MMSET is a focal point for therapeutic interventions against multiple myeloma and especially for t(4;14) myeloma, which is associated with a significantly worse prognosis than other biological subgroups. Multiple myeloma is the second most common hematological malignancy in the United States, after non-Hodgkin lymphoma. Herein, we investigated the in vitro mechanisms of histone mark recognition and modifications by the SET domain of the NSDs and identify novel HMTase inhibitors by virtual ligand screening that may pave the way to specific NSD2/MMSET inhibitors suitable for therapeutic efforts against malignancies that include multiple myeloma. Our data highlights the versatility of NSD1, NSD2, and NSD3 in recognizing and methylating lysine marks on H3 and H4. We report for the discovery of LEM-07 an inhibitor of NSD2/MMSET with an IC50 of 11.2 μM against H3K36 methylation in vitro. LEM-07 would be useful to explore the biology of NSD2. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A123. Citation Format: Eric Di Luccio, Masayo Morishita, Damiaan Mevius, Yunpeng Chen. Structure-function studies and drug design on the histone lysine methyl methyltransferases NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L1. [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 A123.