Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTRA6BO)

• DTT Name: Bromodomain-containing protein 4 (BRD4)
• Synonyms: Protein HUNK1; HUNK1
• Gene Name: BRD4
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Bromodomain
• UniProt ID: BRD4_HUMAN
• TTD ID: T40556
• Sequence:
  MSAESGPGTRLRNLPVMGDGLETSQMSTTQAQAQPQPANAASTNPPPPETSNPNKPKRQT
  NQLQYLLRVVLKTLWKHQFAWPFQQPVDAVKLNLPDYYKIIKTPMDMGTIKKRLENNYYW
  NAQECIQDFNTMFTNCYIYNKPGDDIVLMAEALEKLFLQKINELPTEETEIMIVQAKGRG
  RGRKETGTAKPGVSTVPNTTQASTPPQTQTPQPNPPPVQATPHPFPAVTPDLIVQTPVMT
  VVPPQPLQTPPPVPPQPQPPPAPAPQPVQSHPPIIAATPQPVKTKKGVKRKADTTTPTTI
  DPIHEPPSLPPEPKTTKLGQRRESSRPVKPPKKDVPDSQQHPAPEKSSKVSEQLKCCSGI
  LKEMFAKKHAAYAWPFYKPVDVEALGLHDYCDIIKHPMDMSTIKSKLEAREYRDAQEFGA
  DVRLMFSNCYKYNPPDHEVVAMARKLQDVFEMRFAKMPDEPEEPVVAVSSPAVPPPTKVV
  APPSSSDSSSDSSSDSDSSTDDSEEERAQRLAELQEQLKAVHEQLAALSQPQQNKPKKKE
  KDKKEKKKEKHKRKEEVEENKKSKAKEPPPKKTKKNNSSNSNVSKKEPAPMKSKPPPTYE
  SEEEDKCKPMSYEEKRQLSLDINKLPGEKLGRVVHIIQSREPSLKNSNPDEIEIDFETLK
  PSTLRELERYVTSCLRKKRKPQAEKVDVIAGSSKMKGFSSSESESSSESSSSDSEDSETE
  MAPKSKKKGHPGREQKKHHHHHHQQMQQAPAPVPQQPPPPPQQPPPPPPPQQQQQPPPPP
  PPPSMPQQAAPAMKSSPPPFIATQVPVLEPQLPGSVFDPIGHFTQPILHLPQPELPPHLP
  QPPEHSTPPHLNQHAVVSPPALHNALPQQPSRPSNRAAALPPKPARPPAVSPALTQTPLL
  PQPPMAQPPQVLLEDEEPPAPPLTSMQMQLYLQQLQKVQPPTPLLPSVKVQSQPPPPLPP
  PPHPSVQQQLQQQPPPPPPPQPQPPPQQQHQPPPRPVHLQPMQFSTHIQQPPPPQGQQPP
  HPPPGQQPPPPQPAKPQQVIQHHHSPRHHKSDPYSTGHLREAPSPLMIHSPQMSQFQSLT
  HQSPPQQNVQPKKQELRAASVVQPQPLVVVKEEKIHSPIIRSEPFSPSLRPEPPKHPESI
  KAPVHLPQRPEMKPVDVGRPVIRPPEQNAPPPGAPDKDKQKQEPKTPVAPKKDLKIKNMG
  SWASLVQKHPTTPSSTAKSSSDSFEQFRRAAREKEEREKALKAQAEHAEKEKERLRQERM
  RSREDEDALEQARRAHEEARRRQEQQQQQRQEQQQQQQQQAAAVAAAATPQAQSSQPQSM
  LDQQRELARKREQERRRREAMAATIDMNFQSDLLSIFEENLF
• Function: Chromatin reader protein that recognizes and binds acetylated histones and plays a key role in transmission of epigenetic memory across cell divisions and transcription regulation. Remains associated with acetylated chromatin throughout the entire cell cycle and provides epigenetic memory for postmitotic G1 gene transcription by preserving acetylated chromatin status and maintaining high-order chromatin structure. During interphase, plays a key role in regulating the transcription of signal-inducible genes by associating with the P-TEFb complex and recruiting it to promoters. Also recruits P-TEFb complex to distal enhancers, so called anti-pause enhancers in collaboration with JMJD6. BRD4 and JMJD6 are required to form the transcriptionally active P-TEFb complex by displacing negative regulators such as HEXIM1 and 7SKsnRNA complex from P-TEFb, thereby transforming it into an active form that can then phosphorylate the C-terminal domain (CTD) of RNA polymerase II. Promotes phosphorylation of 'Ser-2' of the C-terminal domain (CTD) of RNA polymerase II. According to a report, directly acts as an atypical protein kinase and mediates phosphorylation of 'Ser-2' of the C-terminal domain (CTD) of RNA polymerase II; these data however need additional evidences in vivo. In addition to acetylated histones, also recognizes and binds acetylated RELA, leading to further recruitment of the P-TEFb complex and subsequent activation of NF-kappa-B. Also acts as a regulator of p53/TP53-mediated transcription: following phosphorylation by CK2, recruited to p53/TP53 specific target promoters.
• Reactome Pathway: Potential therapeutics for SARS (R-HSA-9679191)

Molecular Interaction Atlas (MIA) of This DTT

10 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CPI-0610	DMPXOYJ	Myelofibrosis	2A20.2	Phase 3	[1]
INCB57643	DMBGU7V	Advanced malignancy	2A00-2F9Z	Phase 1/2	[2]
OTX-015	DMI8RG1	Acute myeloid leukaemia	2A60	Phase 1/2	[1]
PLX2853	DMX168L	Acute myeloid leukaemia	2A60	Phase 1/2	[2]
RVX-208	DM1LO8K	Alzheimer disease	8A20	Phase 1/2	[1]
(+)-JQ1	DM1CZSJ	Testicular cancer	2C80	Phase 1	[3]
ABBV-744	DMTEA9C	Acute myeloid leukaemia	2A60	Phase 1	[2]
AZD5153	DMW4GM2	Solid tumour/cancer	2A00-2F9Z	Phase 1	[2]
GSK525762	DMPAWBN	Haematological malignancy	2B33.Y	Phase 1	[1]
TEN010	DM4UOY5	Advanced solid tumour	2A00-2F9Z	Phase 1	[1]

32 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Aminocyclopentenone compound 1	DMYHRJD	N. A.	N. A.	Patented	[4]
Aminocyclopentenone compound 2	DMAYHNI	N. A.	N. A.	Patented	[4]
Aminocyclopentenone compound 3	DMFXK03	N. A.	N. A.	Patented	[4]
Aminocyclopentenone compound 4	DM745TN	N. A.	N. A.	Patented	[4]
Aminocyclopentenone compound 5	DMPW9ES	N. A.	N. A.	Patented	[4]
Aminocyclopentenone compound 6	DM0NJFZ	N. A.	N. A.	Patented	[4]
Benzothiazepine analog 10	DMR6XF4	N. A.	N. A.	Patented	[4]
Benzothiazepine analog 11	DMVC51O	N. A.	N. A.	Patented	[4]
Benzothiazepine analog 12	DM7XQ18	N. A.	N. A.	Patented	[4]
PMID26924192-Compound-102	DMEJ107	N. A.	N. A.	Patented	[4]
PMID26924192-Compound-103	DMWOCP7	N. A.	N. A.	Patented	[4]
PMID26924192-Compound-104	DM346EU	N. A.	N. A.	Patented	[4]
PMID26924192-Compound-105	DMAWLGI	N. A.	N. A.	Patented	[4]
PMID26924192-Compound-20	DMHAOF1	N. A.	N. A.	Patented	[4]
PMID26924192-Compound-21	DM4MZ29	N. A.	N. A.	Patented	[4]
PMID26924192-Compound-22	DMX964E	N. A.	N. A.	Patented	[4]
PMID26924192-Compound-23	DME60LY	N. A.	N. A.	Patented	[4]
PMID26924192-Compound-24	DMDN5Q4	N. A.	N. A.	Patented	[4]
PMID26924192-Compound-25	DMEL7XA	N. A.	N. A.	Patented	[4]
PMID26924192-Compound-30	DMWXNIJ	N. A.	N. A.	Patented	[4]
PMID26924192-Compound-31	DMIFV58	N. A.	N. A.	Patented	[4]
PMID26924192-Compound-32	DM0JSOZ	N. A.	N. A.	Patented	[4]
PMID26924192-Compound-33	DM9NWXM	N. A.	N. A.	Patented	[4]
Pyrazole and thiophene derivative 1	DMKTFJ2	N. A.	N. A.	Patented	[4]
Pyrazole and thiophene derivative 2	DMD51HM	N. A.	N. A.	Patented	[4]
Pyrazole and thiophene derivative 3	DMIKUN9	N. A.	N. A.	Patented	[4]
Pyrazole and thiophene derivative 4	DMDETKY	N. A.	N. A.	Patented	[4]
Pyrrolo-pyrrolone derivative 1	DMN4SE5	N. A.	N. A.	Patented	[4]
Pyrrolo-pyrrolone derivative 2	DM8VYMA	N. A.	N. A.	Patented	[4]
Pyrrolo-pyrrolone derivative 3	DMHGPU1	N. A.	N. A.	Patented	[4]
Pyrrolo-pyrrolone derivative 4	DMFJBZI	N. A.	N. A.	Patented	[4]
Pyrrolo-pyrrolone derivative 5	DMMX0N5	N. A.	N. A.	Patented	[4]

18 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BzT-7	DMU13BY	Discovery agent	N.A.	Investigative	[5]
CPI-203	DMXSYTA	Discovery agent	N.A.	Investigative	[6]
GW841819X	DMRL9IN	Discovery agent	N.A.	Investigative	[7]
I-BET151	DMYRUH2	Discovery agent	N.A.	Investigative	[8]
isoxazole azepine compound 3	DMAFC3R	Discovery agent	N.A.	Investigative	[9]
MS417	DMXC30P	Discovery agent	N.A.	Investigative	[10]
MS436	DMNBFX0	Discovery agent	N.A.	Investigative	[11]
PFI-1	DMVFK3J	Discovery agent	N.A.	Investigative	[12]
PMID21851057C4d	DMI1FGV	Discovery agent	N.A.	Investigative	[13]
PMID23517011C9	DMFQVNL	Discovery agent	N.A.	Investigative	[14]
PMID24000170C36	DMHUWZS	Discovery agent	N.A.	Investigative	[15]
PMID24000170C38	DMOLRIY	Discovery agent	N.A.	Investigative	[15]
PMID25408830C1	DM5GL23	Discovery agent	N.A.	Investigative	[16]
PMID25408830C2	DM20E13	Discovery agent	N.A.	Investigative	[16]
PMID25408830C3	DM8SBR2	Discovery agent	N.A.	Investigative	[16]
PMID25703523C7d	DM4PZ37	Discovery agent	N.A.	Investigative	[17]
XD1	DMS3TZ5	Discovery agent	N.A.	Investigative	[18]
XD14	DMUMACD	Discovery agent	N.A.	Investigative	[18]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Coronary artery disease	BA80-BA8Z	Peripheral blood	3.93E-01	0.06	0.32
Myelodysplastic syndrome	2C82	Bone marrow	3.27E-01	0.02	0.04

References

• [1] Targeting bromodomains: epigenetic readers of lysine acetylation.Nat Rev Drug Discov.2014 May;13(5):337-56.
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] Selective inhibition of BET bromodomains. Nature. 2010 Dec 23;468(7327):1067-73.
• [4] BET inhibitors in cancer therapeutics: a patent review.Expert Opin Ther Pat. 2016;26(4):505-22.
• [5] Benzodiazepines and benzotriazepines as protein interaction inhibitors targeting bromodomains of the BET family. Bioorg Med Chem. 2012 Mar 15;20(6):1878-86.
• [6] BRD4 is an atypical kinase that phosphorylates serine2 of the RNA polymerase II carboxy-terminal domain. Proc Natl Acad Sci U S A. 2012 May 1;109(18):6927-32.
• [7] Discovery and characterization of small molecule inhibitors of the BET family bromodomains. J Med Chem. 2011 Jun 9;54(11):3827-38.
• [8] Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature. 2011 Oct 2;478(7370):529-33.
• [9] Discovery, Design, and Optimization of Isoxazole Azepine BET Inhibitors. ACS Med Chem Lett. 2013 Jul 16;4(9):835-40.
• [10] Down-regulation of NF- B transcriptional activity in HIV-associated kidney disease by BRD4 inhibition. J Biol Chem. 2012 Aug 17;287(34):28840-51.
• [11] Structure-guided design of potent diazobenzene inhibitors for the BET bromodomains. J Med Chem. 2013 Nov 27;56(22):9251-64.
• [12] Identification of a chemical probe for bromo and extra C-terminal bromodomain inhibition through optimization of a fragment-derived hit. J Med Chem. 2012 Nov 26;55(22):9831-7.
• [13] 3,5-dimethylisoxazoles act as acetyl-lysine-mimetic bromodomain ligands. J Med Chem. 2011 Oct 13;54(19):6761-70.
• [14] Optimization of 3,5-dimethylisoxazole derivatives as potent bromodomain ligands. J Med Chem. 2013 Apr 25;56(8):3217-27.
• [15] Naphthyridines as novel BET family bromodomain inhibitors. ChemMedChem. 2014 Mar;9(3):580-9.
• [16] 1,3-Dimethyl Benzimidazolones Are Potent, Selective Inhibitors of the BRPF1 Bromodomain. ACS Med Chem Lett. 2014 Sep 10;5(11):1190-5.
• [17] 9H-purine scaffold reveals induced-fit pocket plasticity of the BRD9 bromodomain. J Med Chem. 2015 Mar 26;58(6):2718-36.
• [18] 4-Acyl pyrroles: mimicking acetylated lysines in histone code reading. Angew Chem Int Ed Engl. 2013 Dec 23;52(52):14055-9.