Histone Methyl Transferase (HMTase) Inhibitor

Histone lysine methylation plays important roles in the organization of chromatin domains and the regulation of gene expression. Among histone lysine methyltransferases (HKMTs) in mammals, G9a and G9a like protein (GLP) are the primary enzymes for mono- and dimethylation at Lys 9 of histone H3 (H3K9me1 and H3K9me2, respectively) and exist for the most part as a G9a–GLP heteromeric complex.¹⁾
BIX 01294 (1) inhibits H3K9 methylation by GLP, G9a HKMTs,^2,3) and H3K36 methylation by oncoproteins⁴⁾ (Table). The inhibition is caused by binding of 1 to the substrate peptide groove of GLP.³⁾ 1 can improve the reprogramming efficiency of mouse embryonic fibroblasts or fetal neural progenitor cells to induced pluripotent stem cells without using c-Myc and SOX2.^5,6)

Table. Inhibition of methylation by 1

References

• 1) H3K9 methyltransferase G9a and the related molecule GLP
• Y. Shinkai, M. Tachibana, Gene Dev. 2011, 25, 781.
• 2) Reversal of H3K9me2 by a Small-Molecule Inhibitor for the G9a Histone Methyltransferase
• S. Kubicek, R. J. O’Sullivan, E. M. August, E. R. Hickey, Q. Zhang, M. L. Teodoro, S. Rea, K. Mechtler, J. A. Kowalski, C. A. Homon, T. A. Kelly, T. Jenuwein, Mol. Cell 2007, 25, 473.
• 3) Structural basis for G9a-like protein lysine methyltransferase inhibition by BIX-01294
• Y. Chang, X. Zhang, J. R. Horton, A. K. Upadhyay, A. Spannhoff, J. Liu, J. P. Snyder, M. T. Bedford, X. Cheng, Nat. Struct. Mol. Biol. 2009, 16, 312.
• 4) BIX-01294 inhibits oncoproteins NSD1, NSD2, and NSD3
• M. Morishita, D. E. H. F. Mevius, Y. Shen, S. Zhao, E. di Luccio, Med. Chem. Res. 2017, 26, 2038.
• 5) Induction of Pluripotent Stem Cells from Mouse Embryonic Fibroblasts by Oct4 and Klf4 with Small-Molecule Compounds
• Y. Shi, C. Desponts, J. T. Do, H. S. Hahm, H. R. Schöler, S. Ding, Cell Stem Cell 2008, 3, 568.
• 6) A Combined Chemical and Genetic Approach for the Generation of Induced Pluripotent Stem Cells
• Y. Shi, J. T. Do, C. Desponts, H. S. Hahm, H. R. Schöler, S. Ding, Cell Stem Cell 2008, 2, 525.

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