Nuclear receptor binding SET domain protein 1 (NSD1), which is a family member of histone methyltransferases, functions to methylate histone H3 on lysine 36 (H3K36). NSD1-related abnormalities are the major cause of Sotos syndrome, and also known to be associated with other human diseases. Inhibitors targeting histone methyltransferases DOT1L and EZH2 have been reported recently. However, no chemical probes targeting NSD1 have been found so far. Here, we identified three hits targeting the NSD1 SET domain using ligand-observed nuclear magnetic resonance (NMR) fragment-based screening. The binding affinities of the hit compounds to the NSD1 SET domain were determined by dose-dependent chemical shift perturbation analysis. Furthermore, the potential binding modes of the hit compounds to NSD1 were obtained by molecular docking. The hit compound 1 was found to bind to the binding pocket of S-adenosylmethionine (SAM), an endogenous ligand of the protein, in the NSD1 SET domain. The study provided valuable information for further structure-guided hit-to-lead evolution towards the potent and specific inhibitors of the NSD1 SET domain.

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sotos sadenosylmethionine receptor binding set domain protein structureguided hittolead evolution pocket dosedependent chemical shift perturbation ezh2 ligandobserved nuclear magnetic resonance nmr histone methyltransferases dot1l

TANG Heng, Gilbert NSHOGOZA,LIU Ming-qing,LIU Ya-qian,RUAN Ke, MA Rong-sheng,GAO Jia,.Identification of Novel Hits of the NSD1 SET Domain by NMR Fragment-Based Screening. 36 (2),.

TANG Heng, Gilbert NSHOGOZA,LIU Ming-qing,LIU Ya-qian,RUAN Ke, MA Rong-sheng,GAO Jia,"Identification of Novel Hits of the NSD1 SET Domain by NMR Fragment-Based Screening" 36

TANG Heng, Gilbert NSHOGOZA,LIU Ming-qing,LIU Ya-qian,RUAN Ke, MA Rong-sheng,GAO Jia,"Identification of Novel Hits of the NSD1 SET Domain by NMR Fragment-Based Screening"