Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTRJ1K4)

• DTT Name: Toll-like receptor 7 (TLR7)
• Synonyms: Toll-like receptor 7
• Gene Name: TLR7
• DTT Type: Successful target; [1]
• Related Disease:
  Malaria [ICD-11: 1F40-1F45]
  Skin cancer [ICD-11: 2C30-2C37]
• BioChemical Class: Toll-like receptor
• UniProt ID: TLR7_HUMAN
• TTD ID: T46482
• Sequence:
  MVFPMWTLKRQILILFNIILISKLLGARWFPKTLPCDVTLDVPKNHVIVDCTDKHLTEIP
  GGIPTNTTNLTLTINHIPDISPASFHRLDHLVEIDFRCNCVPIPLGSKNNMCIKRLQIKP
  RSFSGLTYLKSLYLDGNQLLEIPQGLPPSLQLLSLEANNIFSIRKENLTELANIEILYLG
  QNCYYRNPCYVSYSIEKDAFLNLTKLKVLSLKDNNVTAVPTVLPSTLTELYLYNNMIAKI
  QEDDFNNLNQLQILDLSGNCPRCYNAPFPCAPCKNNSPLQIPVNAFDALTELKVLRLHSN
  SLQHVPPRWFKNINKLQELDLSQNFLAKEIGDAKFLHFLPSLIQLDLSFNFELQVYRASM
  NLSQAFSSLKSLKILRIRGYVFKELKSFNLSPLHNLQNLEVLDLGTNFIKIANLSMFKQF
  KRLKVIDLSVNKISPSGDSSEVGFCSNARTSVESYEPQVLEQLHYFRYDKYARSCRFKNK
  EASFMSVNESCYKYGQTLDLSKNSIFFVKSSDFQHLSFLKCLNLSGNLISQTLNGSEFQP
  LAELRYLDFSNNRLDLLHSTAFEELHKLEVLDISSNSHYFQSEGITHMLNFTKNLKVLQK
  LMMNDNDISSSTSRTMESESLRTLEFRGNHLDVLWREGDNRYLQLFKNLLKLEELDISKN
  SLSFLPSGVFDGMPPNLKNLSLAKNGLKSFSWKKLQCLKNLETLDLSHNQLTTVPERLSN
  CSRSLKNLILKNNQIRSLTKYFLQDAFQLRYLDLSSNKIQMIQKTSFPENVLNNLKMLLL
  HHNRFLCTCDAVWFVWWVNHTEVTIPYLATDVTCVGPGAHKGQSVISLDLYTCELDLTNL
  ILFSLSISVSLFLMVMMTASHLYFWDVWYIYHFCKAKIKGYQRLISPDCCYDAFIVYDTK
  DPAVTEWVLAELVAKLEDPREKHFNLCLEERDWLPGQPVLENLSQSIQLSKKTVFVMTDK
  YAKTENFKIAFYLSHQRLMDEKVDVIILIFLEKPFQKSKFLQLRKRLCGSSVLEWPTNPQ
  AHPYFWQCLKNALATDNHVAYSQVFKETV
• Function: Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. TLR7 is a nucleotide-sensing TLR which is activated by single-stranded RNA. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (By similarity).
• KEGG Pathway:
  Toll-like receptor signaling pathway (hsa04620)
  Measles (hsa05162)
  Influenza A (hsa05164)
• Reactome Pathway:
  TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling (R-HSA-975110)
  TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation (R-HSA-975138)
  MyD88 dependent cascade initiated on endosome (R-HSA-975155)
  Trafficking and processing of endosomal TLR (R-HSA-1679131)

Molecular Interaction Atlas (MIA) of This DTT

2 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Hydroxychloroquine	DMSIVND	Malaria	1F40-1F45	Approved	[2]
Imiquimod	DM1TMA3	Skin cancer	2C30-2C37	Approved	[1]

19 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ANA773	DMSC8YW	Hepatitis C virus infection	1E51.1	Phase 2a	[3]
AZD-8848	DM0M7QW	Allergic rhinitis	CA08.0	Phase 2	[4]
GS-9620	DMG5C8D	Hepatitis B virus infection	1E51.0	Phase 2	[5]
GSK2245035	DMBWPZJ	Asthma	CA23	Phase 2	[6]
IMO-3100	DMM549D	Psoriasis vulgaris	EA90	Phase 2	[7]
Isatoribine	DMHOJ8W	Hepatitis C virus infection	1E51.1	Phase 2	[8]
LOXORIBINE	DMIV9ZE	Immune System disease	4A01-4B41	Phase 2	[9], [10]
PF-4878691	DM24I0N	Melanoma	2C30	Phase 2	[11]
Resiquimod	DML6XSP	Actinic keratosis	EK90.0	Phase 2	[12]
BNT411	DMGF2PU	Small-cell lung cancer	2C25.Y	Phase 1/2	[13]
DSP-0509	DM7WK6N	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[14]
NKTR-262	DMYR8LF	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[15]
CPG 52364	DMVDYTG	Systemic lupus erythematosus	4A40.0	Phase 1	[16]
CV8102	DMYD37G	Melanoma	2C30	Phase 1	[17]
DV-1179	DMDSVRP	Autoimmune disease	4A40-4A45	Phase 1	[18]
LHC165	DMYK52O	Solid tumour/cancer	2A00-2F9Z	Phase 1	[19]
MEDI9197	DM0J7UR	Solid tumour/cancer	2A00-2F9Z	Phase 1	[20]
RG6115	DM6TLPD	Hepatocellular carcinoma	2C12.02	Phase 1	[21]
RG7854	DMGLXQ9	Hepatitis B virus infection	1E51.0	Phase 1	[21]

3 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
IM0-8400	DMEF9JW	Diffuse large B-cell lymphoma	2A81	Discontinued in Phase 1/2	[22]
ANA-975	DMFR3PD	Immune System disease	4A01-4B41	Discontinued in Phase 1	[8]
IPH-3201	DM7J8IO	Solid tumour/cancer	2A00-2F9Z	Terminated	[23]

3 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
TMX-201	DMULO0V	Autoimmune diabetes	5A10	Investigative	[23]
TMX-202	DMPX3WT	Bladder cancer	2C94	Investigative	[23]
TMX-30X	DMSEAMU	Autoimmune diabetes	5A10	Investigative	[23]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Asthma	CA23	Nasal and bronchial airway	1.11E-02	0.18	0.28
Skin cancer	2C82	Skin	3.32E-25	0.44	0.88
Bladder cancer	2C82	Bladder tissue	2.06E-03	-0.69	-2.35

References

• [1] Imiquimod enhances IFN-gamma production and effector function of T cells infiltrating human squamous cell carcinomas of the skin. J Invest Dermatol. 2009 Nov;129(11):2676-85.
• [2] TLR7/9 antagonists as therapeutics for immune-mediated inflammatory disorders. Inflamm Allergy Drug Targets. 2007 Dec;6(4):223-35.
• [3] Clinical pipeline report, company report or official report of Anadys Pharmaceuticals (2011).
• [4] Repeated intranasal TLR7 stimulation reduces allergen responsiveness in allergic rhinitis. Respir Res. 2012 Jun 22;13:53.
• [5] Pharmacokinetic and pharmacodynamic properties of GS-9620, a novel Toll-like receptor 7 agonist, demonstrate interferon-stimulated gene induction without detectable serum interferon at low oral doses. J Pharmacol Exp Ther. 2014 Jan;348(1):96-105.
• [6] Early clinical evaluation of the intranasal TLR7 agonist GSK2245035: Use of translational biomarkers to guide dosing and confirm target engagement. Clin Pharmacol Ther. 2015 Oct;98(4):369-80.
• [7] Company report (Iderapharma)
• [8] Discovery of ANA975: an oral prodrug of the TLR-7 agonist isatoribine. Nucleosides Nucleotides Nucleic Acids. 2007;26(6-7):635-40.
• [9] The Toll-like receptor 7 (TLR7)-specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily. Eur J Immunol. 2003 Nov;33(11):2987-97.
• [10] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [11] The innate immune response, clinical outcomes, and ex vivo HCV antiviral efficacy of a TLR7 agonist (PF-4878691). Clin Pharmacol Ther. 2011 Jun;89(6):821-9.
• [12] TLR agonists as vaccine adjuvants: comparison of CpG ODN and Resiquimod (R-848).Vaccine.2005 Nov 1;23(45):5263-70.
• [13] Clinical pipeline report, company report or official report of BioNTech.
• [14] Clinical pipeline report, company report or official report of Sumitomo Dainippon Pharma.
• [15] Clinical pipeline report, company report or official report of Nektar Therapeutics.
• [16] Coley Pharmaceutical Group Diversifies Pipeline with First-in-Class TLR Antagonist for the Treatment of Systemic Lupus Erythematosus. Lupus Foundation of America, Inc. 2007.
• [17] Clinical pipeline report, company report or official report of CureVac.
• [18] Company report (Dynavax)
• [19] Agonist and antagonist ligands of toll-like receptors 7 and 8: Ingenious tools for therapeutic purposes. Eur J Med Chem. 2020 May 1;193:112238.
• [20] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [21] Clinical pipeline report, company report or official report of Roche.
• [22] Clinical pipeline report, company report or official report of Idera Pharmaceuticals.
• [23] 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. (Target id: 1757).