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Literature summary for 2.1.1.366 extracted from
- SETDB1, an H3K9-specific methyltransferase An attractive epigenetic target to combat cancer (2024), Drug Discov. Today, 29, 103982.
Inhibitors
| Inhibitors | Comment | Organism | Structure |
|---|---|---|---|
| 1-methyl-5H-[1,2,4]triazolo[4,3-a][3,1]benzoxazine | SETDB1-TTD inhibitor, binds to the acetyl lysine (Kac) pocket of the SETDB1-TTD | Homo sapiens |  |
| 1-[(3,4-dimethoxyphenyl)methyl]-4-[[2-(trifluoromethyl)-7H-pyrrolo[2,3-b]pyridin-7-yl]methyl]piperidin-4-ol | peptidecompetitive SETDB1 inhibitor, decreases SETDB1/ESET levels without changing the mRNA levels (FRET) and exerts noticeable inhibitory effects on H3K9 trimethylation. Induces neuronal cytotoxicity at 0.1 mM | Homo sapiens | |
| 2-([5-[4-(benzyloxy)phenyl]-1-methylpiperidin-3-yl]amino)-3-(prop-2-en-1-yl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one | SETDB1-TTD inhibitor, inhibits the interaction of H3 peptide with the SETDB1-TTD | Homo sapiens | |
| 3,3-dimethyl-1-[(3S)-1,2,3,4-tetrahydroisoquinolin-3-yl]butan-1-one | SETDB1-TTD inhibitor, very weak binding in the aromatic cage of the dimethyl lysine (Kme2) pocket of the SETDB1-TTD | Homo sapiens | |
| 5-[(prop-2-en-1-yl)oxy]-2-(pyrrolidin-1-yl)quinoline | SETDB1 SET domain inhibitor, inhibits SETDB1 activity and H3K9me3 expression, and improves motor function and neuropathological symptoms with minimal toxicity in mouse HD models | Homo sapiens | |
| 7-chloro-2-[3-(dimethylamino)propyl]-1-(3-ethoxyphenyl)-1,2,3a,9a-tetrahydro[1]benzopyrano[2,3-c]pyrrole-3,9-dione | peptidecompetitive SETDB1 inhibitor, decreases H3K9me3 levels and shows neuronal effects without cytotoxicity | Homo sapiens | |
| N-[(furan-2-yl)methyl]-1-[(3S)-1,2,3,4-tetrahydroisoquinoline-3-carbonyl]piperidine-4-carboxamide | SETDB1-TTD inhibitor, binds in the aromatic cage | Homo sapiens | |
| N-[2-(diethylamino)ethyl]-2-([5,7-dimethyl-6-[(2-methylphenyl)methyl][1,2,4]triazolo[1,5-a]pyrimidin-2-yl]sulfanyl)acetamide | competitive SETDB1 inhibitor, decreases H3K9me3 levels and shows neuronal effects without cytotoxicity | Homo sapiens | |
| N-[[1,1'-bi(cyclohexan)]-4-yl]-6-methoxy-7-[3-(piperidin-1-yl)propoxy]-2-[4-(propan-2-yl)-1,4-diazepan-1-yl]quinazolin-4-amine | competitive inhibition, the inhibitor docks in the Tudor domain | Homo sapiens | |
| N-[[2-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)cyclohexyl]methyl]acetamide | SETDB1-TTD inhibitor, binds in the aromatic cage of the Kac pocket of the SETDB1-TTD. It displayed weak binding by SPR and ITC | Homo sapiens | |
| N2-(3'-[[4-(4-butylpiperazin-1-yl)pyridine-2-carbonyl]amino][1,1'-biphenyl]-4-carbonyl)-6-pyrrolidin-1-yl-L-norleucinamide | SETDB1-TTD inhibitor, shows competitive inhibition and docked between the Tudor 2 and 3 | Homo sapiens | |
| N2-(3'-[[4-(4-butylpiperazin-1-yl)pyridine-2-carbonyl]amino][1,1'-biphenyl]-4-carbonyl)-N6,N6-dimethyl-L-lysinamide | SETDB1-TTD inhibitor, shows competitive inhibition and docks between the Tudor 2 and 3 domains | Homo sapiens | |
| N2-(3'-[[4-(4-methylpiperazin-1-yl)pyridine-2-carbonyl]amino][1,1'-biphenyl]-4-carbonyl)-6-pyrrolidin-1-yl-L-norleucinamide | SETDB1-TTD inhibitor, shows competitive inhibition and docks between the Tudor 2 and 3 domains | Homo sapiens | |
| N2-[3'-[(4-[4-[3-(dimethylamino)propyl]piperazin-1-yl]pyridine-2-carbonyl)amino][1,1'-biphenyl]-4-carbonyl]-6-pyrrolidin-1-yl-L-norleucinamide | SETDB1-TTD inhibitor, shows competitive inhibition and docks between the Tudor 2 and 3 domains | Homo sapiens | |
| N2-[3'-[(4-[4-[3-(dimethylamino)propyl]piperazin-1-yl]pyridine-2-carbonyl)amino][1,1'-biphenyl]-4-carbonyl]-N6,N6-dimethyl-L-lysinamide | SETDB1-TTD inhibitor, shows competitive inhibition and docks between the Tudor 2 and 3 domains | Homo sapiens | |
| N4-[6-(dimethylamino)hexyl]-N2-[5-(dimethylamino)pentyl]-6,7-dimethoxyquinazoline-2,4-diamine | SETDB1-TTD inhibitor, shows competitive inhibition and docks between the Tudor 2 and 3 domains | Homo sapiens | |
| N6,N6-dimethyl-L-lysyl-L-serylthreonyl-N-([4-[2-(acetamidomethyl)cyclohexyl]-4H-1,2,4-triazol-3-yl]methyl)glycinamide | - |
Homo sapiens | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Homo sapiens | Q15047 | - |
- |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| SET domain bifurcated histone lysine methyltransferase 1 | - |
Homo sapiens |
| SETDB1 | - |
Homo sapiens |
IC50 Value
| IC50 Value | IC50 Value Maximum | Comment | Organism | Inhibitor | Structure |
|---|---|---|---|---|---|
| 0.0008 | - |
pH and temperature not specified in the publication | Homo sapiens | N2-[3'-[(4-[4-[3-(dimethylamino)propyl]piperazin-1-yl]pyridine-2-carbonyl)amino][1,1'-biphenyl]-4-carbonyl]-6-pyrrolidin-1-yl-L-norleucinamide | |
| 0.0012 | - |
pH and temperature not specified in the publication | Homo sapiens | N2-[3'-[(4-[4-[3-(dimethylamino)propyl]piperazin-1-yl]pyridine-2-carbonyl)amino][1,1'-biphenyl]-4-carbonyl]-N6,N6-dimethyl-L-lysinamide | |
| 0.0023 | - |
pH and temperature not specified in the publication | Homo sapiens | N-[[1,1'-bi(cyclohexan)]-4-yl]-6-methoxy-7-[3-(piperidin-1-yl)propoxy]-2-[4-(propan-2-yl)-1,4-diazepan-1-yl]quinazolin-4-amine | |
| 0.0031 | - |
pH and temperature not specified in the publication | Homo sapiens | N2-(3'-[[4-(4-butylpiperazin-1-yl)pyridine-2-carbonyl]amino][1,1'-biphenyl]-4-carbonyl)-N6,N6-dimethyl-L-lysinamide | |
| 0.0032 | - |
pH and temperature not specified in the publication | Homo sapiens | N2-(3'-[[4-(4-butylpiperazin-1-yl)pyridine-2-carbonyl]amino][1,1'-biphenyl]-4-carbonyl)-6-pyrrolidin-1-yl-L-norleucinamide | |
| 0.0034 | - |
pH and temperature not specified in the publication | Homo sapiens | N4-[6-(dimethylamino)hexyl]-N2-[5-(dimethylamino)pentyl]-6,7-dimethoxyquinazoline-2,4-diamine | |
| 0.0035 | - |
pH and temperature not specified in the publication | Homo sapiens | N2-(3'-[[4-(4-methylpiperazin-1-yl)pyridine-2-carbonyl]amino][1,1'-biphenyl]-4-carbonyl)-6-pyrrolidin-1-yl-L-norleucinamide | |
Expression
| Organism | Comment | Expression |
|---|---|---|
| Homo sapiens | SETDB1 is overexpressed in a significant proportion of melanoma cases | up |
General Information
| General Information | Comment | Organism |
|---|---|---|
| drug target | downregulating SETDB1 is an attractive therapeutic option in AKT-driven cancer and for enhancing the immunotherapeutic response | Homo sapiens |
| malfunction | aberrant SETDB1 expression, and its oncogenic role is evident in many cancers. Amplified SETDB1 is associated with enhanced tumorigenesis and poor prognosis in a wide variety of cancers. This increased oncogenic effect is probably due to a SETDB1 methylation-associated suppressive effect on various tumor suppressors, AKT hyperactivation, and increased mutant p53 stability. SETDB1 overexpression shows a significant negative correlation with immunomodulatory outcomes through tumor immune evasion and IFN-I pathway repression | Homo sapiens |
| physiological function | the enzyme is involved in various regulatory processes such as cell proliferation, progression, migration, survival, and apoptosis. The enzyme is an important epigenetic regulator catalyzing histone H3 lysine 9 (H3K9) methylation, specifically di-/tri-methylation. This regulation promotes gene silencing through heterochromatin formation. SETDB1 altered lymphocyte and cytokine expression, disrupts the IFN-I response, promotes TAM recruitment, induces ERV silencing, and facilitates tumor immune escape | Homo sapiens |
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