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; UNC Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery, Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Shell DJ; UNC Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery, Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Silva M; University of Toronto, Toronto, ON, Canada.; Deng Y; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.; Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Li F; University of Toronto, Toronto, ON, Canada.; Szewczyk MM; University of Toronto, Toronto, ON, Canada.; Yang K; Department of Cell Biology, Harvard Medical School, Boston, MA, USA.; Zhao Y; UNC Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery, Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Stashko MA; UNC Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery, Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Norris-Drouin JL; UNC Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery, Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Waybright JM; UNC Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery, Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Design Therapeutics, Carlsbad, CA, USA.; Beldar S; University of Toronto, Toronto, ON, Canada.; Rectenwald JM; UNC Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery, Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Mordant AL; UNC Metabolomics and Proteomics Core Facility, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Webb TS; UNC Metabolomics and Proteomics Core Facility, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Herring LE; UNC Metabolomics and Proteomics Core Facility, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Arrowsmith CH; University of Toronto, Toronto, ON, Canada.; Ackloo S; University of Toronto, Toronto, ON, Canada.; Gygi SP; Department of Cell Biology, Harvard Medical School, Boston, MA, USA.; McGinty RK; UNC Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery, Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.; Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Barsyte-Lovejoy D; University of Toronto, Toronto, ON, Canada.; Liu P; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.; Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Halabelian L; University of Toronto, Toronto, ON, Canada.; James LI; UNC Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery, Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.; Pearce KH; UNC Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery, Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.; Frye SV; UNC Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery, Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. svfrye@email.unc.edu.; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. svfrye@email.unc.edu. |
| Source: | Nature communications [Nat Commun] 2025 Feb 24; Vol. 16 (1), pp. 1905. Date of Electronic Publication: 2025 Feb 24. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [London] : Nature Pub. Group |
| MeSH Terms: | Histone-Lysine N-Methyltransferase*/metabolism ; Histone-Lysine N-Methyltransferase*/antagonists & inhibitors ; Histone-Lysine N-Methyltransferase*/chemistry ; Histone-Lysine N-Methyltransferase*/genetics; Allosteric Regulation/drug effects ; Methylation/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; Humans ; Ligands ; HEK293 Cells ; Binding Sites |
| Abstract: | A promising drug target, SETDB1, is a dual methyl-lysine (Kme) reader and methyltransferase 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 identify a low micromolar potency small molecule ligand, UNC6535, which occupies simultaneously both the TD2 and TD3 reader binding sites. Further optimization leads to the discovery of UNC10013, a covalent 3TD ligand targeting Cys385 of SETDB1. UNC10013 is potent with a kinact/KI of 1.0 × 106 M-1s-1 and demonstrates proteome-wide selectivity. In cells, negative allosteric modulation of SETDB1-mediated Akt methylation occurs 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.; (© 2025. The Author(s).) |
| Competing Interests: | Competing interests: The authors declare no competing interests. |
| Comments: | Update of: bioRxiv. 2024 Sep 28:2024.09.27.615363. doi: 10.1101/2024.09.27.615363.. (PMID: 39386588) |
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| Grant Information: | R35 GM133498 United States GM NIGMS NIH HHS; P30 CA016086 United States CA NCI NIH HHS; R35 GM139514 United States GM NIGMS NIH HHS; P30CA016086 U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI); R35GM139514 U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) |
| Substance Nomenclature: | EC 2.1.1.43 (Histone-Lysine N-Methyltransferase); EC 2.1.1.43 (SETDB1 protein, human); 0 (Ligands); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) |
| Entry Date(s): | Date Created: 20250224 Date Completed: 20250509 Latest Revision: 20250722 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC11850789 |
| DOI: | 10.1038/s41467-025-57005-3 |
| PMID: | 39994194 |
| Database: | MEDLINE |
Journal Article