SETDB1 Triple Tudor Domain Ligand, ( R,R )-59, Promotes Methylation of Akt1 in Cells.
| Title: | SETDB1 Triple Tudor Domain Ligand, ( R,R )-59, Promotes Methylation of Akt1 in Cells. |
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| Authors: | Uguen M; Deng Y; Li F; Shell DJ; Norris-Drouin JL; Stashko MA; Ackloo S; Arrowsmith CH; James LI; Liu P; Pearce KH; Frye SV |
| Source: | BioRxiv : the preprint server for biology [bioRxiv] 2023 May 10. Date of Electronic Publication: 2023 May 10. |
| Publication Type: | Preprint; Journal Article |
| Language: | English |
| Journal Info: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet ISSN: 2692-8205 (Electronic) Linking ISSN: 26928205 NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| Abstract: | Increased expression and hyperactivation of the methyltransferase 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 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 SAM binding. |
| Comments: | Update in: ACS Chem Biol. 2023 Aug 18;18(8):1846-1853. doi: 10.1021/acschembio.3c00280.. (PMID: 37556795) |
| Entry Date(s): | Date Created: 20230522 Latest Revision: 20230818 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC10197638 |
| DOI: | 10.1101/2023.05.10.539986 |
| PMID: | 37214894 |
| Database: | MEDLINE |
Preprint; Journal Article