Potent and Selective SETDB1 Covalent Negative Allosteric Modulator Reduces Methyltransferase Activity in Cells.
| Title: | Potent and Selective SETDB1 Covalent Negative Allosteric Modulator Reduces Methyltransferase Activity in Cells. |
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| Authors: | Uguen M; Shell DJ; Silva M; Deng Y; Li F; Szewczyk MM; Yang K; Zhao Y; Stashko MA; Norris-Drouin JL; Waybright JM; Beldar S; Rectenwald JM; Mordant AL; Webb TS; Herring LE; Arrowsmith CH; Ackloo S; Gygi SP; McGinty RK; Barsyte-Lovejoy D; Liu P; Halabelian L; James LI; Pearce KH; Frye SV |
| Source: | BioRxiv : the preprint server for biology [bioRxiv] 2024 Sep 28. Date of Electronic Publication: 2024 Sep 28. |
| Publication Type: | Journal Article; Preprint |
| 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: | A promising drug target, SETDB1, is a dual Kme reader and methyltransferase, which has been implicated in cancer and neurodegenerative disease progression. To help understand the role of the triple Tudor domain (3TD) of SETDB1, its Kme reader, we first identified a low micromolar small molecule ligand, UNC6535, which occupies simultaneously both the TD2 and TD3 reader binding sites. Further optimization led to the discovery of UNC10013, the first covalent 3TD ligand targeting Cys385 of SETDB1. UNC10013 is potent with a k inact /K I of 1.0 x 10 6 M -1 s -1 and demonstrated proteome-wide selectivity. In cells, negative allosteric modulation of SETDB1-mediated Akt methylation was observed after treatment with UNC10013. Therefore, UNC10013 is a potent, selective and cell-active covalent ligand for the 3TD of SETDB1, demonstrating negative allosteric modulator properties and making it a promising tool to study the biological role of SETDB1 in disease progression. |
| Comments: | Update in: Nat Commun. 2025 Feb 24;16(1):1905. doi: 10.1038/s41467-025-57005-3.. (PMID: 39994194) |
| Entry Date(s): | Date Created: 20241010 Latest Revision: 20250509 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC11463403 |
| DOI: | 10.1101/2024.09.27.615363 |
| PMID: | 39386588 |
| Database: | MEDLINE |
Journal Article; Preprint