Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTGC95K)

• DTT Name: SET domain containing 8 (KMT5A)
• Synonyms: SETD8; SET8; SET07; SET domain-containing protein 8; PRSET7; PR/SET07; PR/SET domain-containing protein 07; PR-Set7; N-lysine methyltransferase KMT5A; Lysine-specific methylase 5A; Lysine N-methyltransferase 5A; Histone-lysine N-methyltransferase KMT5A; H4-K20-HMTase KMT5A
• Gene Name: KMT5A
• DTT Type: Preclinical target; [1]
• BioChemical Class: Methyltransferase
• UniProt ID: KMT5A_HUMAN
• TTD ID: T30420
• EC Number: EC 2.1.1.-
• Sequence:
  MGEGGAAAALVAAAAAAAAAAAAVVAGQRRRRLGRRARCHGPGRAAGGKMSKPCAVEAAA
  AAVAATAPGPEMVERRGPGRPRTDGENVFTGQSKIYSYMSPNKCSGMRFPLQEENSVTHH
  EVKCQGKPLAGIYRKREEKRNAGNAVRSAMKSEEQKIKDARKGPLVPFPNQKSEAAEPPK
  TPPSSCDSTNAAIAKQALKKPIKGKQAPRKKAQGKTQQNRKLTDFYPVRRSSRKSKAELQ
  SEERKRIDELIESGKEEGMKIDLIDGKGRGVIATKQFSRGDFVVEYHGDLIEITDAKKRE
  ALYAQDPSTGCYMYYFQYLSKTYCVDATRETNRLGRLINHSKCGNCQTKLHDIDGVPHLI
  LIASRDIAAGEELLYDYGDRSKASIEAHPWLKH
• Function: Specifically monomethylates 'Lys-20' of histone H4 (H4K20me1). H4K20me1 is enriched during mitosis and represents a specific tag for epigenetic transcriptional repression. Mainly functions in euchromatin regions, thereby playing a central role in the silencing of euchromatic genes. Required for cell proliferation, probably by contributing to the maintenance of proper higher-order structure of DNA during mitosis. Involved in chromosome condensation and proper cytokinesis. Nucleosomes are preferred as substrate compared to free histones. Mediates monomethylation of p53/TP53 at 'Lys-382', leading to repress p53/TP53-target genes. Plays a negative role in TGF-beta response regulation and a positive role in cell migration. Protein-lysine N-methyltransferase that monomethylates both histones and non-histone proteins.
• KEGG Pathway:
  Lysine degradation (hsa00310)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  PKMTs methylate histone lysines (R-HSA-3214841)
  Regulation of TP53 Activity through Methylation (R-HSA-6804760)
  Condensation of Prophase Chromosomes (R-HSA-2299718)
• BioCyc Pathway: MetaCyc:HS11381-MON

Molecular Interaction Atlas (MIA) of This DTT

2 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
MS2177	DMDEJBQ	Solid tumour/cancer	2A00-2F9Z	Preclinical	[2]
UNC0379	DMD1E4J	Hepatocellular carcinoma	2C12.02	Preclinical	[2]

2 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
MS453	DMBTPDL	Discovery agent	N.A.	Investigative	[3]
nahuoic acid A	DM1LWMU	Discovery agent	N.A.	Investigative	[1]

References

• [1] Nahuoic acid A produced by a Streptomyces sp. isolated from a marine sediment is a selective SAM-competitive inhibitor of the histone methyltransferase SETD8. Org Lett. 2013 Jan 18;15(2):414-7.
• [2] Epigenetics and beyond: targeting writers of protein lysine methylation to treat disease. Nat Rev Drug Discov. 2021 Apr;20(4):265-286.
• [3] Structure-Based Design of a Covalent Inhibitor of the SET Domain-Containing Protein 8 (SETD8) Lysine Methyltransferase. J Med Chem. 2016 Nov 10;59(21):9881-9889.