BET N-terminal bromodomain inhibition selectively blocks Th17 cell differentiation and ameliorates colitis in mice

• DOI: 10.1073/pnas.1615601114
• Publication Date: 2017-03-07T02:00:34Z
• Authors: Kalung Cheung; Geming Lu; Rajal Sharma; Adam Vincek; Ruihua Zhang; Alexander N. Plot...; Fan Zhang; Qiang Zhang; Ying Ju; Yuan Hu; Li Zhao; Xinye Han; Jamel Meslamani; Feihong Xu; Anbalagan Jaganathan; Tong Shen; Hongfa Zhu; Elena Rusinova; Lei Zeng; Jiachi Zhou; Jianjun Yang; Liang Peng; Michael Ohlmeyer; Martin J. Walsh; David Y. Zhang; Huabao Xiong; Ming-Ming Zhou
• Keywords: Mice, Knockout; 0301 basic medicine; Magnetic Resonance Spectroscopy; Computational Biology; Proteins; Cell Differentiation; Colitis; Ligands; Disease Models, Animal; Mice; 03 medical and health sciences; T-Lymphocyte Subsets; Animals; Humans; Th17 Cells; Protein Interaction Domains and Motifs

Significance

The bromodomain and extraterminal domain (BET) proteins regulate transcription of subset-specifying genes during lineage-specific T-helper-cell differentiation in adaptor immunity and are also implicated in inflammatory disorders. The available pan-BET bromodomain inhibitors such as JQ1 indiscriminately block the tandem bromodomains (BD1 and BD2) of the BET proteins, broadly render differentiation of different Th subsets, and have limited therapeutic potential. Here we report a small molecule, MS402, that can selectively inhibit BD1 over BD2 of the BET proteins and block Th17 maturation from mouse naive CD4 + T cells, with limited or no effects on Th1, Th2, or Treg cells. MS402 effectively prevents and ameliorates T-cell transfer-induced colitis in mice by disrupting Th17 cell development, thus representing a therapeutic approach for inflammatory bowel diseases.