Drug Information

Drug (ID: DG01501) and It's Reported Resistant Information

• Name: Tofacitinib
• Synonyms: Tofacitinib; Tasocitinib; 477600-75-2; 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile; CP-690550; CP 690550; 1259404-17-5; rac-Tofacitinib; CP-690,550; UNII-87LA6FU830; Tofacitinib (CP-690550,Tasocitinib); 3-((3R,4R)-rel-4-Methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile; racemic-tofacitinib; 3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile; CP690550; CHEMBL221959; CHEBI:71200; 87LA6FU830; 477600-75-2 (free base); MFCD11035919; 3-((3R,4R)-4-Methyl-3-(methyl(7H-pyrrolo(2,3-d)pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile; 3-[(3R*,4R*)-4-Methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropanenitrile; 3-[(3R,4R)-4-methyl-3-[methyl({7H-pyrrolo[2,3-d]pyrimidin-4-yl})amino]piperidin-1-yl]-3-oxopropanenitrile; 3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropanenitrile; 3-{(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile; Tofacitinib [USAN:INN]; C16H20N6O; tofacitinibum; 3eyg; 3fup; 3lxk; 4oti; MI1; Tofacitinib (USAN); Cp-690 free base; 1-Piperidinepropanenitrile, 4-methyl-3-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-beta-oxo-, (3R,4R)-; SCHEMBL322753; Tofacitinib (CP-690550); GTPL5677; QCR-53; HSDB 8311; AMY3992; DTXSID90197271; EX-A205; BCPP000274; CP-690550 FREE BASE; AOB87470; ZINC3818808; CP-690,550 FREE BASE; BDBM50193995; CP-690; NSC782351; NSC800953; s2789; AKOS005145814; AKOS005258733; AC-8193; BCP9000550; CA10005; CCG-264998; CS-0050; DB08895; GS-6106; NSC-782351; NSC-800953; NCGC00229511-02; NCGC00229511-04; NCGC00229511-10; NCGC00244463-01; Tofacitinib (CP-690550, Tasocitinib); HY-40354; CP690,550; CP-690-550; W6440; CP- 690 550; D09970; AB01565786_02; 600M752; AR-270/43507983; J-524314; Q3530324; BRD-K31283835-001-01-9; BRD-K31283835-048-04-4; 3-((3R,4R)-4-Methyl(7H-Pyrrolo[2,3-D]Pyrimidin-4-Yi)Amino)Piperidin-1-Yl-3-Oxopropaneni; (3R,4R)-3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile; (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-beta-oxo-1-piperidine propanenitrile; 3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-1-piperidyl]-3-oxo-propanenitrile; 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]piperidin-1-yl}-3-oxo-propionitrile; 3-{(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile; 3-{4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-1-piperidinyl}-3-oxopropanenitrile; 3-Piperidinamine, 1-(cyanoacetyl)-4-methyl-N-methyl-N-1H-pyrrolo(2,3-d)pyrimidin-4-yl-, (3R,4R)-; Tofacitinib;3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile
• Indication:
  In total 1 Indication(s)
  Rheumatoid arthritis [ICD-11: FA20]; Discontinued in Phase 2; [1]
• Target: Janus kinase 3 (JAK-3); JAK3_HUMAN; [1]
• Formula: 3
• IsoSMILES: C[C@@H]1CCN(C[C@@H]1N(C)C2=NC=NC3=C2C=CN3)C(=O)CC#N
• InChI: InChI=1S/C16H20N6O/c1-11-5-8-22(14(23)3-6-17)9-13(11)21(2)16-12-4-7-18-15(12)19-10-20-16/h4,7,10-11,13H,3,5,8-9H2,1-2H3,(H,18,19,20)/t11-,13+/m1/s1
• InChIKey: UJLAWZDWDVHWOW-YPMHNXCESA-N
• PubChem CID: 9926791
• ChEBI ID: CHEBI:71200
• DrugBank ID: DB08895

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase JAK3 (JAK3) [1]

• Molecule Alteration: Missense mutation; p.L857P (c.2570T>C)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: U4C cells; Acetabulum; Homo sapiens (Human); CVCL_D314
• In Vivo Model: Balb/c bone marrow transplantation mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Proliferation assay

Key Molecule: Tyrosine-protein kinase JAK3 (JAK3) [2]

• Molecule Alteration: Missense mutation; p.E183G (c.548A>G)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.E183G (c.548A>G) in gene JAK3 cause the sensitivity of Tofacitinib by aberration of the drug's therapeutic target

Key Molecule: Tyrosine-protein kinase JAK3 (JAK3) [1]

• Molecule Alteration: Missense mutation; p.V674A (c.2021T>C)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: U4C cells; Acetabulum; Homo sapiens (Human); CVCL_D314
• In Vivo Model: Balb/c bone marrow transplantation mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Proliferation assay

Key Molecule: Tyrosine-protein kinase JAK3 (JAK3) [2]

• Molecule Alteration: Missense mutation; p.A572V (c.1715C>T)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.A572V (c.1715C>T) in gene JAK3 cause the sensitivity of Tofacitinib by aberration of the drug's therapeutic target

Key Molecule: Tyrosine-protein kinase JAK3 (JAK3) [2]

• Molecule Alteration: Missense mutation; p.L156P (c.467T>C)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.L156P (c.467T>C) in gene JAK3 cause the sensitivity of Tofacitinib by aberration of the drug's therapeutic target

Key Molecule: Tyrosine-protein kinase JAK3 (JAK3) [2]

• Molecule Alteration: Missense mutation; p.R172Q (c.515G>A)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.R172Q (c.515G>A) in gene JAK3 cause the sensitivity of Tofacitinib by aberration of the drug's therapeutic target

Key Molecule: Tyrosine-protein kinase JAK3 (JAK3) [3]

• Molecule Alteration: Missense mutation; p.V722I (c.2164G>A)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Trypan blue exclusion assay

Mature T-cell and Nk-cell lymphoma [ICD-11: 2B0Y]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase JAK3 (JAK3) [4]

• Molecule Alteration: Missense mutation; p.A572V (c.1715C>T)
• Sensitive Disease: Mature T-cell and Nk-cell lymphoma [ICD-11: 2B0Y.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: NK-S1 cells; N.A.; .; N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The missense mutation p.A572V (c.1715C>T) in gene JAK3 cause the sensitivity of Tofacitinib by aberration of the drug's therapeutic target

Hematologic cancer [ICD-11: 2B3Z]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tyrosine-protein kinase JAK3 (JAK3) [5]

• Molecule Alteration: Missense mutation; p.M511I (c.1533G>C)
• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay; FACS assay
• Mechanism Description: Jak3 inhibitors CP-690,550 and NC1153 showed efficacy in reducing viability of Ba/F3 cells transformed with mutant forms of Jak3.

Key Molecule: Tyrosine-protein kinase JAK3 (JAK3) [5]

• Molecule Alteration: Missense mutation; p.A573V (c.1718C>T)
• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay; FACS assay
• Mechanism Description: Jak3 inhibitors CP-690,550 and NC1153 showed efficacy in reducing viability of Ba/F3 cells transformed with mutant forms of Jak3.

Key Molecule: Tyrosine-protein kinase JAK3 (JAK3) [6]

• Molecule Alteration: Missense mutation; p.H583Y (c.1747C>T)
• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JAKT/STAT signaling pathway; Inhibition; hsa04630
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: NIH-3T3 cells; Embryo; Mus musculus (Mouse); CVCL_0594
• Experiment for Molecule Alteration: Immunohistochemistry assay; Immunoblotting assay
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: A STAT3 inhibitor was active against STAT3 -mutant SNK-6 and YT cells. Novel JAK3 mutations are oncogenic and druggable in NTCL. The JAK3 or STAT3 signal was altered in NTCL, and pathway inhibition might be a therapeutic option for patients with JAK3 - or STAT3 -mutant NTCL.

Key Molecule: Tyrosine-protein kinase JAK3 (JAK3) [6]

• Molecule Alteration: Missense mutation; p.G589D (c.1766G>A)
• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JAKT/STAT signaling pathway; Inhibition; hsa04630
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: NIH-3T3 cells; Embryo; Mus musculus (Mouse); CVCL_0594
• Experiment for Molecule Alteration: Immunohistochemistry assay; Immunoblotting assay
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: A STAT3 inhibitor was active against STAT3 -mutant SNK-6 and YT cells. Novel JAK3 mutations are oncogenic and druggable in NTCL. The JAK3 or STAT3 signal was altered in NTCL, and pathway inhibition might be a therapeutic option for patients with JAK3 - or STAT3 -mutant NTCL.

References

• Ref 1: Distinct Acute Lymphoblastic Leukemia (ALL)-associated Janus Kinase 3 (JAK3) Mutants Exhibit Different Cytokine-Receptor Requirements and JAK Inhibitor SpecificitiesJ Biol Chem. 2015 Nov 27;290(48):29022-34. doi: 10.1074/jbc.M115.670224. Epub 2015 Oct 7.
• Ref 2: FERM domain mutations induce gain of function in JAK3 in adult T-cell leukemia/lymphomaBlood. 2011 Oct 6;118(14):3911-21. doi: 10.1182/blood-2010-12-319467. Epub 2011 Aug 5.
• Ref 3: Identification of mutant alleles of JAK3 in pediatric patients with acute lymphoblastic leukemiaLeuk Lymphoma. 2015 May;56(5):1502-6. doi: 10.3109/10428194.2014.957204. Epub 2015 Jan 21.
• Ref 4: Janus kinase 3-activating mutations identified in natural killer/T-cell lymphomaCancer Discov. 2012 Jul;2(7):591-7. doi: 10.1158/2159-8290.CD-12-0028. Epub 2012 Jun 15.
• Ref 5: Transforming Mutations of Jak3 (A573V and M511I) Show Differential Sensitivity to Selective Jak3 InhibitorsClin Cancer Drugs. 2016;3(2):131-137. doi: 10.2174/2212697X03666160610085943.
• Ref 6: Novel JAK3-Activating Mutations in Extranodal NK/T-Cell Lymphoma, Nasal TypeAm J Pathol. 2017 May;187(5):980-986. doi: 10.1016/j.ajpath.2017.01.004. Epub 2017 Mar 9.