Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTSZ8T1)

• DTT Name: Histone-lysine N-methyltransferase (HLNM)
• Synonyms: Lysine N-methyltransferase 4; KMT4; KIAA1814; Histone-lysine N-methyltransferase, H3 lysine-79 specific; Histone H3-K79 methyltransferase; H3-K79-HMTase; DOT1-like protein
• Gene Name: DOT1L
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Methyltransferase
• UniProt ID: DOT1L_HUMAN
• TTD ID: T87686
• EC Number: EC 2.1.1.43
• Sequence:
  MGEKLELRLKSPVGAEPAVYPWPLPVYDKHHDAAHEIIETIRWVCEEIPDLKLAMENYVL
  IDYDTKSFESMQRLCDKYNRAIDSIHQLWKGTTQPMKLNTRPSTGLLRHILQQVYNHSVT
  DPEKLNNYEPFSPEVYGETSFDLVAQMIDEIKMTDDDLFVDLGSGVGQVVLQVAAATNCK
  HHYGVEKADIPAKYAETMDREFRKWMKWYGKKHAEYTLERGDFLSEEWRERIANTSVIFV
  NNFAFGPEVDHQLKERFANMKEGGRIVSSKPFAPLNFRINSRNLSDIGTIMRVVELSPLK
  GSVSWTGKPVSYYLHTIDRTILENYFSSLKNPKLREEQEAARRRQQRESKSNAATPTKGP
  EGKVAGPADAPMDSGAEEEKAGAATVKKPSPSKARKKKLNKKGRKMAGRKRGRPKKMNTA
  NPERKPKKNQTALDALHAQTVSQTAASSPQDAYRSPHSPFYQLPPSVQRHSPNPLLVAPT
  PPALQKLLESFKIQYLQFLAYTKTPQYKASLQELLGQEKEKNAQLLGAAQQLLSHCQAQK
  EEIRRLFQQKLDELGVKALTYNDLIQAQKEISAHNQQLREQSEQLEQDNRALRGQSLQLL
  KARCEELQLDWATLSLEKLLKEKQALKSQISEKQRHCLELQISIVELEKSQRQQELLQLK
  SCVPPDDALSLHLRGKGALGRELEPDASRLHLELDCTKFSLPHLSSMSPELSMNGQAAGY
  ELCGVLSRPSSKQNTPQYLASPLDQEVVPCTPSHVGRPRLEKLSGLAAPDYTRLSPAKIV
  LRRHLSQDHTVPGRPAASELHSRAEHTKENGLPYQSPSVPGSMKLSPQDPRPLSPGALQL
  AGEKSSEKGLRERAYGSSGELITSLPISIPLSTVQPNKLPVSIPLASVVLPSRAERARST
  PSPVLQPRDPSSTLEKQIGANAHGAGSRSLALAPAGFSYAGSVAISGALAGSPASLTPGA
  EPATLDESSSSGSLFATVGSRSSTPQHPLLLAQPRNSLPASPAHQLSSSPRLGGAAQGPL
  PEASKGDLPSDSGFSDPESEAKRRIVFTITTGAGSAKQSPSSKHSPLTASARGDCVPSHG
  QDSRRRGRRKRASAGTPSLSAGVSPKRRALPSVAGLFTQPSGSPLNLNSMVSNINQPLEI
  TAISSPETSLKSSPVPYQDHDQPPVLKKERPLSQTNGAHYSPLTSDEEPGSEDEPSSARI
  ERKIATISLESKSPPKTLENGGGLAGRKPAPAGEPVNSSKWKSTFSPISDIGLAKSADSP
  LQASSALSQNSLFTFRPALEEPSADAKLAAHPRKGFPGSLSGADGLSPGTNPANGCTFGG
  GLAADLSLHSFSDGASLPHKGPEAAGLSSPLSFPSQRGKEGSDANPFLSKRQLDGLAGLK
  GEGSRGKEAGEGGLPLCGPTDKTPLLSGKAAKARDREVDLKNGHNLFISAAAVPPGSLLS
  GPGLAPAASSAGGAASSAQTHRSFLGPFPPGPQFALGPMSLQANLGSVAGSSVLQSLFSS
  VPAAAGLVHVSSAATRLTNSHAMGSFSGVAGGTVGGN
• Function: Histone methyltransferase. Methylates 'Lys-79' of histone H3. Nucleosomes are preferred as substrate compared to free histones. Binds to DNA.
• KEGG Pathway:
  Lysine degradation (hsa00310)
  Transcriptional misregulation in cancer (hsa05202)
• Reactome Pathway: PKMTs methylate histone lysines (R-HSA-3214841)
• BioCyc Pathway: MetaCyc:HS02643-MON

Molecular Interaction Atlas (MIA) of This DTT

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
EPZ-5676	DMN2FS3	Acute myeloid leukaemia	2A60	Phase 1/2	[1]

3 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
bromo-deaza-SAH	DMX2U7G	Discovery agent	N.A.	Investigative	[2]
EPZ-004777	DMLN4V5	leukaemia	2A60-2B33	Investigative	[3]
SGC0946	DMP35VS	Discovery agent	N.A.	Investigative	[4]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Acute myelocytic leukaemia	2C82	Bone marrow	7.62E-02	0.08	0.2

References

• [1] Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood. 2013 August 8; 122(6): 1017-1025.
• [2] Bromo-deaza-SAH: a potent and selective DOT1L inhibitor. Bioorg Med Chem. 2013 Apr 1;21(7):1787-94.
• [3] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7377).
• [4] Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors. Nat Commun. 2012;3:1288.