Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTT7PJU)

• DTT Name: Janus kinase 3 (JAK-3)
• Synonyms: Tyrosine-protein kinase JAK3; Leukocyte janus kinase; L-JAK
• Gene Name: JAK3
• DTT Type: Successful target; [1]
• BioChemical Class: Kinase
• UniProt ID: JAK3_HUMAN
• TTD ID: T23172
• EC Number: EC 2.7.10.2
• Sequence:
  MAPPSEETPLIPQRSCSLLSTEAGALHVLLPARGPGPPQRLSFSFGDHLAEDLCVQAAKA
  SGILPVYHSLFALATEDLSCWFPPSHIFSVEDASTQVLLYRIRFYFPNWFGLEKCHRFGL
  RKDLASAILDLPVLEHLFAQHRSDLVSGRLPVGLSLKEQGECLSLAVLDLARMAREQAQR
  PGELLKTVSYKACLPPSLRDLIQGLSFVTRRRIRRTVRRALRRVAACQADRHSLMAKYIM
  DLERLDPAGAAETFHVGLPGALGGHDGLGLLRVAGDGGIAWTQGEQEVLQPFCDFPEIVD
  ISIKQAPRVGPAGEHRLVTVTRTDNQILEAEFPGLPEALSFVALVDGYFRLTTDSQHFFC
  KEVAPPRLLEEVAEQCHGPITLDFAINKLKTGGSRPGSYVLRRSPQDFDSFLLTVCVQNP
  LGPDYKGCLIRRSPTGTFLLVGLSRPHSSLRELLATCWDGGLHVDGVAVTLTSCCIPRPK
  EKSNLIVVQRGHSPPTSSLVQPQSQYQLSQMTFHKIPADSLEWHENLGHGSFTKIYRGCR
  HEVVDGEARKTEVLLKVMDAKHKNCMESFLEAASLMSQVSYRHLVLLHGVCMAGDSTMVQ
  EFVHLGAIDMYLRKRGHLVPASWKLQVVKQLAYALNYLEDKGLPHGNVSARKVLLAREGA
  DGSPPFIKLSDPGVSPAVLSLEMLTDRIPWVAPECLREAQTLSLEADKWGFGATVWEVFS
  GVTMPISALDPAKKLQFYEDRQQLPAPKWTELALLIQQCMAYEPVQRPSFRAVIRDLNSL
  ISSDYELLSDPTPGALAPRDGLWNGAQLYACQDPTIFEERHLKYISQLGKGNFGSVELCR
  YDPLGDNTGALVAVKQLQHSGPDQQRDFQREIQILKALHSDFIVKYRGVSYGPGRQSLRL
  VMEYLPSGCLRDFLQRHRARLDASRLLLYSSQICKGMEYLGSRRCVHRDLAARNILVESE
  AHVKIADFGLAKLLPLDKDYYVVREPGQSPIFWYAPESLSDNIFSRQSDVWSFGVVLYEL
  FTYCDKSCSPSAEFLRMMGCERDVPALCRLLELLEEGQRLPAPPACPAEVHELMKLCWAP
  SPQDRPSFSALGPQLDMLWSGSRGCETHAFTAHPEGKHHSLSFS
• Function: Mediates essential signaling events in both innate and adaptive immunity and plays a crucial role in hematopoiesis during T-cells development. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors sharing the common subunit gamma such as IL2R, IL4R, IL7R, IL9R, IL15R and IL21R. Following ligand binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins. Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, upon IL2R activation by IL2, JAK1 and JAK3 molecules bind to IL2R beta (IL2RB) and gamma chain (IL2RG) subunits inducing the tyrosine phosphorylation of both receptor subunits on their cytoplasmic domain. Then, STAT5A AND STAT5B are recruited, phosphorylated and activated by JAK1 and JAK3. Once activated, dimerized STAT5 translocates to the nucleus and promotes the transcription of specific target genes in a cytokine-specific fashion. Non-receptor tyrosine kinase involved in various processes such as cell growth, development, or differentiation.
• KEGG Pathway:
  Chemokine signaling pathway (hsa04062)
  PI3K-Akt signaling pathway (hsa04151)
  Signaling pathways regulating pluripotency of stem cells (hsa04550)
  Jak-STAT signaling pathway (hsa04630)
  Measles (hsa05162)
  HTLV-I infection (hsa05166)
  Epstein-Barr virus infection (hsa05169)
  Viral carcinogenesis (hsa05203)
  Primary immunodeficiency (hsa05340)
• Reactome Pathway:
  Interleukin-7 signaling (R-HSA-1266695)
  G beta (R-HSA-392451)
  Interleukin-2 signaling (R-HSA-451927)
  RAF/MAP kinase cascade (R-HSA-5673001)
  Interleukin receptor SHC signaling (R-HSA-912526)
  GPVI-mediated activation cascade (R-HSA-114604)

Molecular Interaction Atlas (MIA) of This DTT

4 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Abrocitinib	DM8J29L	Atopic dermatitis	EA80	Approved	[2]
Pacritinib	DM1T6ZN	Myelofibrosis	2A20.2	Approved	[3]
Ritlecitinib	DMYKNME	Alopecia areata	ED70.2	Approved	[4]
Tofacitinib	DMBS370	Rheumatoid arthritis	FA20	Approved	[1]

12 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ASP-015K	DMZ1UOI	Psoriasis vulgaris	EA90	Phase 3	[5]
VX-509	DM2U3MX	Rheumatoid arthritis	FA20	Phase 2/3	[6]
ATI-501	DMTY6OF	Alopecia	ED70	Phase 2	[7]
ATI-502	DM8NODR	Alopecia	ED70	Phase 2	[8]
Cerdulatinib	DMSCR2H	B-cell lymphoma	2A86	Phase 2	[4]
TD-8236	DMTOMJN	Asthma	CA23	Phase 2	[9]
ALXN2075	DM1BSD8	Non-hodgkin lymphoma	2B33.5	Phase 1/2	[10]
AZD4604	DMP3CSV	Asthma	CA23	Phase 1	[11]
GDC-0214	DMCNSII	Asthma	CA23	Phase 1	[12]
KN-002	DMK8FHB	Severe asthma	CA23	Phase 1	[13]
PF-07295324	DMBE63K	Atopic dermatitis	EA80	Phase 1	[14]
SNA-125	DM8L1GJ	Atopic dermatitis	EA80	Phase 1	[4]

65 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
1,2,4-triazolo[1,5a]pyridine derivative 1	DMIUPSA	N. A.	N. A.	Patented	[15]
Aminooxazole carboxamide derivative 1	DMDHGPN	N. A.	N. A.	Patented	[16]
Aminotriazolopyridine derivative 1	DMW2LZ0	N. A.	N. A.	Patented	[15]
Benzimidazole derivative 5	DMWOJLX	N. A.	N. A.	Patented	[16]
Benzimidazole derivative 7	DMDK4RI	N. A.	N. A.	Patented	[15]
Bis-aminopyrimidine derivative 1	DMQL34C	N. A.	N. A.	Patented	[15]
Bis-aminopyrimidine derivative 2	DMJXNO1	N. A.	N. A.	Patented	[15]
Bis-aminopyrimidine derivative 3	DMUNSYX	N. A.	N. A.	Patented	[15]
Bis-aminopyrimidine derivative 4	DMO1ZIG	N. A.	N. A.	Patented	[15]
Five-and-six-membered heterocyclic compound 1	DM7SK5Q	N. A.	N. A.	Patented	[16]
Imidazopyridazine derivative 1	DMEY6L8	N. A.	N. A.	Patented	[15]
Imidazopyridazine derivative 2	DMZORKY	N. A.	N. A.	Patented	[15]
Imidazopyridine derivative 4	DMP2AXV	N. A.	N. A.	Patented	[15]
Imidazo[4,5-c]pyridine derivative 1	DM4KBZQ	N. A.	N. A.	Patented	[15]
Imidazo[4,5-c]pyridine derivative 2	DMFDRJT	N. A.	N. A.	Patented	[15]
Isoxazole derivative 1	DMUMPZX	N. A.	N. A.	Patented	[16]
Isoxazole derivative 2	DMT842O	N. A.	N. A.	Patented	[16]
N-(cyanomethyl)-4-(2-(phenylamino)pyrimidin-4-yl)benzamide derivative 1	DM0OMAL	N. A.	N. A.	Patented	[15]
N-methylmethanesulfonamide derivative 1	DMIVK7D	N. A.	N. A.	Patented	[16]
PMID27774822-Compound-Figure10Example1	DMCTXPQ	N. A.	N. A.	Patented	[16]
PMID27774822-Compound-Figure10Example19	DMNXYZP	N. A.	N. A.	Patented	[16]
PMID27774822-Compound-Figure11Example5	DMAHFXV	N. A.	N. A.	Patented	[16]
PMID27774822-Compound-Figure1Example20	DMCL19N	N. A.	N. A.	Patented	[16]
PMID27774822-Compound-Figure2Example1-1left	DM86M7D	N. A.	N. A.	Patented	[16]
PMID27774822-Compound-Figure2Example1-1right	DM2YPLF	N. A.	N. A.	Patented	[16]
PMID27774822-Compound-Figure2Example4-3	DMEHIS4	N. A.	N. A.	Patented	[16]
PMID27774822-Compound-Figure6Example2	DMCD19T	N. A.	N. A.	Patented	[16]
PMID27774822-Compound-Figure6Example3	DM3FY85	N. A.	N. A.	Patented	[16]
PMID27774822-Compound-Figure8Example5	DMRHZF3	N. A.	N. A.	Patented	[16]
PMID27774824-Compound-Figure11Example1up	DMH1W8F	N. A.	N. A.	Patented	[15]
PMID27774824-Compound-Figure12Example1	DMAGKNJ	N. A.	N. A.	Patented	[15]
PMID27774824-Compound-Figure12Example10	DMYOSIA	N. A.	N. A.	Patented	[15]
PMID27774824-Compound-Figure12Example61	DMNIZD7	N. A.	N. A.	Patented	[15]
PMID27774824-Compound-Figure2Example4	DMQHYMJ	N. A.	N. A.	Patented	[15]
PMID27774824-Compound-Figure3Example18	DMYZ6XQ	N. A.	N. A.	Patented	[15]
PMID27774824-Compound-Figure3Example7	DMXDOGK	N. A.	N. A.	Patented	[15]
PMID27774824-Compound-Figure5Example13	DMDZKXC	N. A.	N. A.	Patented	[15]
PMID27774824-Compound-Figure6Example12	DM1CM7S	N. A.	N. A.	Patented	[15]
PMID27774824-Compound-Figure9Example2down	DMXAV42	N. A.	N. A.	Patented	[15]
PMID27774824-Compound-Figure9Example2up	DME3TMS	N. A.	N. A.	Patented	[15]
Pyrazolopyridine derivative 1	DMY03RZ	N. A.	N. A.	Patented	[16]
Pyrazolopyridine derivative 2	DMCJVLR	N. A.	N. A.	Patented	[16]
Pyrazolopyridine derivative 3	DM2VQ4P	N. A.	N. A.	Patented	[16]
Pyrazolopyridine derivative 4	DMX7RWV	N. A.	N. A.	Patented	[16]
Pyrazolopyridine derivative 6	DM5OH8D	N. A.	N. A.	Patented	[15]
Pyrazolopyridine derivative 7	DMCTQ9O	N. A.	N. A.	Patented	[15]
Pyrazolo[4,3-c]pyridine derivative 2	DMCDFLQ	N. A.	N. A.	Patented	[15]
Pyrimidopyridazinone derivative 2	DMD1RT0	N. A.	N. A.	Patented	[15]
Pyrrole six-membered heteroaryl ring derivative 1	DM1A0VB	N. A.	N. A.	Patented	[16]
Pyrrolo-pyrazine derivative 1	DMP8I02	N. A.	N. A.	Patented	[16]
Pyrrolo-pyrazine derivative 2	DMO9Q8J	N. A.	N. A.	Patented	[16]
Pyrrolo-pyrazine derivative 3	DMLM6DT	N. A.	N. A.	Patented	[16]
Pyrrolo-pyrazine derivative 4	DMD1S92	N. A.	N. A.	Patented	[16]
Pyrrolo-pyridine derivative 3	DMSNQEJ	N. A.	N. A.	Patented	[16]
Pyrrolo[2,3-d]pyrimidine derivative 6	DM3D1L6	N. A.	N. A.	Patented	[16]
Pyrrolo[2,3-d]pyrimidine derivative 7	DM30Y8M	N. A.	N. A.	Patented	[16]
Pyrrolo[2,3-d]pyrimidine derivative 8	DMAW6KU	N. A.	N. A.	Patented	[16]
Ruxolitinib derivative 2	DMSJWZ3	N. A.	N. A.	Patented	[15]
Tricyclic compound 1	DMLBR4F	N. A.	N. A.	Patented	[15]
Tricyclic compound 11	DMJAZ7D	N. A.	N. A.	Patented	[16]
Tricyclic compound 2	DMJAWOI	N. A.	N. A.	Patented	[15]
Tricyclic heterocycle derivative 1	DMXLJH4	N. A.	N. A.	Patented	[16]
Tricyclic heterocycle derivative 2	DM1W02D	N. A.	N. A.	Patented	[15]
Tricyclic heterocycle derivative 5	DMG1ESV	N. A.	N. A.	Patented	[16]
Tricyclic pyrrolopyridine compound 1	DMFIXW4	N. A.	N. A.	Patented	[16]

3 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AG490	DM3WKO5	Multiple myeloma	2A83	Terminated	[17]
PNU156804	DM23ZHN	Renal transplantation	NE84	Terminated	[18]
R348	DM12EYR	Psoriasis vulgaris	EA90	Terminated	[19]

12 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
6-o-tolylquinazolin-2-amine	DM4TX9O	Discovery agent	N.A.	Investigative	[20]
AD-412	DMJMCDP	Autoimmune diabetes	5A10	Investigative	[5]
Atropisomer 1	DML3R5Z	Discovery agent	N.A.	Investigative	[21]
CMP-6	DM241YW	Discovery agent	N.A.	Investigative	[22]
NC1153	DM6XGFE	Renal transplantation	NE84	Investigative	[17]
PF-956980	DMIUZSR	Inflammation	1A00-CA43.1	Investigative	[5]
PMID15546730C2	DMOPUIH	Discovery agent	N.A.	Investigative	[23]
PMID21493067C1d	DMFUQIT	Discovery agent	N.A.	Investigative	[24]
PMID24359159C19a	DM26JYS	Discovery agent	N.A.	Investigative	[25]
VX-467	DM4Q5DO	Inflammation	1A00-CA43.1	Investigative	[5]
WHI-P154	DMYHWS1	Diffuse large B-cell lymphoma	2A81	Investigative	[26]
ZM-39923	DMTMVYH	Discovery agent	N.A.	Investigative	[27]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Rheumatoid arthritis	FA20	Synovial tissue	3.32E-02	0.39	1.32
Multiple myeloma	2C82	Bone marrow	4.94E-03	0.28	1.41
Psoriasis	EA90	Skin	2.54E-02	-0.19	-0.51

References

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• [2] FDA Approved Drug Products from FDA Official Website. 2023. Application Number: 213871.
• [3] FDA Approved Drug Products from FDA Official Website. 2022. Application Number: 208712.
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [5] 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: 2049).
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• [8] ClinicalTrials.gov (NCT03759340) ATI-502 Topical Solution for the Treatment of Alopecia Areata (AA), Alopecia Universalis (AU) and Alopecia Totalis (AT). U.S. National Institutes of Health.
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• [11] Clinical pipeline report, company report or official report of AstraZeneca
• [12] Inhaled JAK inhibitor GDC-0214 reduces exhaled nitric oxide in patients with mild asthma: A?randomized, controlled, proof-of-activity trial. J Allergy Clin Immunol. 2021 Sep;148(3):783-789.
• [13] Clinical pipeline report, company report or official report of Kinaset Therapeutics
• [14] Clinical pipeline report, company report or official report of Pfzer
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• [16] Inhibitors of JAK-family kinases: an update on the patent literature 2013-2015, part 2.Expert Opin Ther Pat. 2017 Feb;27(2):145-161.
• [17] Immunotherapy for De Novo renal transplantation: what's in the pipeline Drugs. 2006;66(13):1665-84.
• [18] Selective inhibitor of Janus tyrosine kinase 3, PNU156804, prolongs allograft survival and acts synergistically with cyclosporine but additively with rapamycin. Blood. 2002 Jan 15;99(2):680-9.
• [19] Emerging drugs for psoriasis. Expert Opin Emerg Drugs. 2009 Mar;14(1):145-63.
• [20] Discovery of aminoquinazolines as potent, orally bioavailable inhibitors of Lck: synthesis, SAR, and in vivo anti-inflammatory activity. J Med Chem. 2006 Sep 21;49(19):5671-86.
• [21] Janus kinase 2 inhibitors. Synthesis and characterization of a novel polycyclic azaindole. J Med Chem. 2009 Dec 24;52(24):7938-41.
• [22] Photochemical preparation of a pyridone containing tetracycle: a Jak protein kinase inhibitor. Bioorg Med Chem Lett. 2002 Apr 22;12(8):1219-23.
• [23] Discovery of novel 2-(aminoheteroaryl)-thiazole-5-carboxamides as potent and orally active Src-family kinase p56(Lck) inhibitors. Bioorg Med Chem Lett. 2004 Dec 20;14(24):6061-6.
• [24] In vitro and in vivo evaluation of 6-aminopyrazolyl-pyridine-3-carbonitriles as JAK2 kinase inhibitors. Bioorg Med Chem Lett. 2011 May 15;21(10):2958-61.
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