SETDB1 Triple Tudor Domain Ligand, (R,R)-59, Promotes Methylation of Akt1 in Cells.

Mélanie Uguen, Yu Deng, Fengling Li, Devan J Shell, Jacqueline L Norris-Drouin, Michael A Stashko, Suzanne Ackloo, Cheryl H Arrowsmith, Lindsey I James, Pengda Liu, Kenneth H Pearce, Stephen V Frye

ACS chemical biology 2023 Aug 18

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Increased expression and hyperactivation of the methyltransferase SET domain bifurcated 1 (SETDB1) are commonly observed in cancer and central nervous system disorders. However, there are currently no reported SETDB1-specific methyltransferase inhibitors in the literature, suggesting that this is a challenging target. Here, we disclose that the previously reported small-molecule ligand for SETDB1's triple tudor domain, (R,R)-59, is unexpectedly able to increase SETDB1 methyltransferase activity both in vitro and in cells. Specifically, (R,R)-59 promotes in vitro SETDB1-mediated methylation of lysine 64 of the protein kinase Akt1. Treatment with (R,R)-59 also increased Akt1 threonine 308 phosphorylation and activation, a known consequence of Akt1 methylation, resulting in stimulated cell proliferation in a dose-dependent manner. (R,R)-59 is the first SETDB1 small-molecule positive activator for the methyltransferase activity of this protein. Mechanism of action studies show that full-length SETDB1 is required for significant in vitro methylation of an Akt1-K64 peptide and that this activity is stimulated by (R,R)-59 primarily through an increase in catalytic activity rather than a change in S-adenosyl methionine binding.

Citation

Mélanie Uguen, Yu Deng, Fengling Li, Devan J Shell, Jacqueline L Norris-Drouin, Michael A Stashko, Suzanne Ackloo, Cheryl H Arrowsmith, Lindsey I James, Pengda Liu, Kenneth H Pearce, Stephen V Frye. SETDB1 Triple Tudor Domain Ligand, (R,R)-59, Promotes Methylation of Akt1 in Cells. ACS chemical biology. 2023 Aug 18;18(8):1846-1853