Methylation of lysine 36 on histone H3 (H3K36me2) by histone lysine methyltransferase (NSD2) constitutes one of the major chromatin regulatory mechanisms<sup>.</sup> Overexpression of NSD2 has been genetically linked to multiple myeloma in various cancers. Despite these findings, no drug candidate has been developed to date.<br/>Our computational analysis of homology model of NSD2 revealed two druggable binding sites – the S-adenosyl-methionine (SAM) and substrate binding pockets. Further biochemical and biophysical characterization of the SAM binding to NSD2 was performed. Subsequent efforts towards developing inhibitors of NSD2 led to the discovery of ligands binding in the low micromolar range. The structure-activity-relationship, as well as proposed binding site and mode will be detailed during presentation.

Characterization of histone lysine methyltransferase and discovery of NSD2 inhibitors

253rd National Meeting (2017)

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