General
Preferred name
tofacitinib
Synonyms
Xeljanz ()
CP 690550 citrate ()
PFE-PKIS 25 ()
Tasocitinib, Tofacitinib Citrate, CP-690, Xeljanz, CP-690550-10, Tasocitinib Citrate, CP-690550 ()
CP-690550 ()
Tasocitinib ()
CP-690550 citrate ()
Tasocitinib citrate ()
Tofacitinib (CP-690550) Citrate ()
TOFACITINIB CITRATE ()
CP 690550 ()
tofacitinib ()
Tasocitinib (citrate) ()
CP-690550 (citrate) ()
tofacitinib (controlled release) ()
Tofacitinib (citrate) ()
550 ()
CP- 690 550 ()
CP-690 ()
CP-690 FREE BASE ()
CP-690,550 ()
CP-690,550 FREE BASE ()
CP-690-550 ()
CP-690550 FREE BASE ()
CP690,550 ()
CP690550 ()
PFE-PKIS_25 ()
Tofacitinib (CP-690550) ()
Tasocitinib Citrate,CP-690550 ()
CP-690,550-10 ()
CP-690550-10 ()
XELJANZ XR ()
TASOCITINIB MONOCITRATE ()
TOFACITINIB MONOCITRATE ()
?Tofacitinib (citrate) ()
Tofacitinib-d3 (citrate) ()
P&D ID
PD004666
CAS
477600-75-2
540737-29-9
1259404-17-5
Tags
available
covalent binder
drug
probe
Approved by
FDA
PMDA
EMA
First approval
2012
Drug indication
Rheumatoid arthritis
Drug Status
withdrawn
approved
investigational
Max Phase
4.0
Probe info
Probe type
experimental probe
calculated probe
Probe sources
Probe targets
[[ compound.targets[t].gene_name ]]
Probe control
Probe control not defined
Orthogonal probes
48
No orthogonal probes found
Similar probes
1
No structurally similar probes found
Structure
P&D probe-likeness score
Structure formats
[[ format ]]
[[ compound[format === 'MOL' ? 'molblock' : format.toLowerCase()] ]]
Description
(extracted from source data)
DESCRIPTION
Tofacitinib is a Type-1 Janus kinase 3 (JAK3) kinase inhibitor and was first approved by the US FDA in 2012. Tofacitinib was refused approval in the EU in 2013.
ABSORPTION
74% oral absorption (absolute bioavailability), with peak plasma concentrations (T max) achieved in 0.5-1 hour. ; ; Administration with fatty meals does not alter AUC but reduces Cmax by 32%.
DESCRIPTION
Tofacitinib is an orally active, Type-1 Janus kinase 3 (JAK3) kinase inhibitor and was first approved by the US FDA in 2012.
MOA
Rheumatoid arthritis is an autoimmune disease characterized by a dysregulation of pro-inflammatory cytokines including IL7, IL15, IL21, IL6, IFN-alpha, and IFN-beta. (3) Cytokines signalling results in tissue inflammation and joint damage by stimulating the recruitment and activation of immune cells via the janus kinase signalling pathway.; ; Tofacitinib is a partial and reversible janus kinase (JAK) inihibitor that will prevent the body from responding to cytokine signals. By inhibiting JAKs, tofacitinib prevents the phosphorylation and activation of STATs. The JAK-STAT signalling pathway is involved in the transcription of cells involved in hematopoiesis, and immune cell function. Tofacitinib works therapeutically by inhibiting the JAK-STAT pathway to decrease the inflammatory response. However, there is evidence to suggest that it may also achieve efficacy via other pathways as well. ; ; ;
INDICATION
For the treatment of moderate to severe rheumatoid arthritis which is resistant or intolerant to methotrexate therapy. It may also be used as an adjunct to methotrexate therapy, or other non-biologic disease-modifying antirheumatic drugs (DMARDS), when methotrexate alone is not sufficient. ; ; Tofacitinib has also been investigated as a preventative therapy for kidney transplant rejections, and as a treatment for psoriasis, ulcerative colitis, and ankylosing spondylitis. ; ; It is not to be initiated in patients with a history of chronic or recurrent infections, or in the presence of active infection, even if localized, due to reports of serious and sometimes fatal infections (commonly pneumonia, herpes zoster and urinary tract infections). Use of tofacitinib is also discouraged in those who have been, or are likely to be, exposed to TB. An increased likelihood of exposure may be encountered by traveling to certain areas. In addition, tofacitinib is not to be used in patients with severe hepatic impairment, or low hemoglobin (less than 9g/dL). Cautioned is advised when using tofacitinib in patients at risk of gastrointestinal perforation, and in the elderly who are more susceptible to infection.
ROE
70% metabolized in the liver by CYP3A4 (major) and CYP2C19 (minor). ; Metabolites produced are inactive. ; 30% renally eliminated as unchanged drug.
DESCRIPTION
Tofacitinib is an orally active, Type-1 Janus kinase (JAK) inhibitor and it was first approved by the US FDA in 2012. Tofacitinib was originally described as a selective JAK3 inhibitor , but subsequent analysis has revealed it to be a pan-JAK inhibitor, with predominant JAK1 inhibition .
(GtoPdb)
PHARMACODYNAMICS
Tofacitinib targets inflammation present in rheumatoid arthritis by inhibiting the janus kinases involved in the inflammatory response pathway. ; ; In placebo controlled trials of rheumatoid arthritis patients receiving 5mg or 10mg of tofacitinib twice daily, higher ACR20 responses were observed within 2 weeks in some patients (with ACR20 being defined as a minimum 20% reduction in joint pain or tenderness and 20% reduction in arthritis pain, patient disability, inflammatory markers, or global assessments of arthritis by patients or by doctors, according to the American College of Rheumatology (ACR) response criteria list), and improvements in physical functioning greater than placebo were also noted. ; ; Common known adverse effects of tofacitinib include headaches, diarrhea, nausea, nasopharyngitis and upper respiratory tract infection. More serious immunologic and hematological adverse effects have also been noted resulting in lymphopenia, neutropenia, anemia, and increased risk of cancer and infection. ; ; Before initiations of tofacitinib patients should be tested for latent infections of tuberculosis, and should be closely monitored for signs and symptoms of infection (fungal, viral, bacterial, or mycobacterial) during therapy. Therapy is not to be started in the presence of active infection, systemic or localized, and is to be interrupted if a serious infection occurs. ; ; Tofacitinib has been associated with an increased risk of lymphomas, such as Epstein-Barr virus associated lymphomas, and other malignancies (including lung, breast, gastric, and colorectal cancers). It is recommended to monitor lymphocytes, neutrophils, hemoglobin, liver enzymes, and lipids. ; ; Tofacitinib use is associated with a rapid decrease in C-reactive protein (CRP), dose dependent decreases in natural killer cells, and dose dependent increases in B cells. Depression in C-reactive protein levels continue after 2 weeks of tofacitinib discontinuation and suggest that pharmacodynamic activity last longer than pharmacokinetic half life.
TOXICITY
Minimum lethal dose in rat: 500 mg/kg. ; Maximum asymptomatic dose in non human primate: 40 mg/kg. ; ; Lymphatic, immune system, bone marrow and erythroid cell toxicity was seen in animal studies involving rate and monkeys. Doses used in these studies ranged from 1mg/kg/day to 10mg/kg/day, over a duration of 6 weeks to 6 months. Lymphopenia, neutropenia, and anemia is seen in human subjects and may call for an interruption or discontinuation of therapy if severe. ; ; Reduced female fertility in rats was seen at exposures 17 times the maximum recommended human dose. Fertility may be impaired in human females and harm may be caused to unborn child. ; Carcinogenic potential is seen, however evidence for dose dependency is lacking.; ; Because the janus kinase pathway plays a role in stimulating the production of red blood cells and is involved in immune cell function, inhibition of this pathway leads to increased risk of anemia, neutropenia, lymphopenia, cancer and infection. ; ; Lymphopenia, neutropenia, and anemia in human subjects may call for an interruption or discontinuation of therapy if severe. ; ; Role of JAK inhibition in the development of gastrointestinal perforation is not known.
COMMENT
This probe will always inhibit both JAK1 and JAK3 at any in vitro and in vivo dose explored. At higher doses, it will inhibit JAK2 , and at even higher doses, it inhibits TYK2. Care in data interpretation and target association is, therefore, warranted within the JAK family of kinases. Jun 16 2016 - 5:44pm; In human primary cell types, tofacitinib is active and non-cytotoxic from 14 nM to 90 uM. Between 14-120 nM, it is active in human primary cell-based assays that are JAK3/JAK1 dependent. At 370 nM and above, it is active in assays that are JAK1/JAK2 dependent (DOI:10.1039/9781782620136-00088). Jun 16 2016 - 5:45pm; There is convincing evidence demonstrating direct target engagement of JAK1, JAK2, JAK3 and TYK2 by tofacitinib in vitro using X-ray crystallography (i.e., PMIDs 20478313, 19361440). Based on the reported IC50 values in cell-free systems, tofacitinib will most likely inhibit JAK1, JAK2 and JAK3 to varying degrees at the recommended concentrations (1-120 nM); therefore, users should be cautious about assuming isoform selectivity in their particular system. The original report (PMID 14593182) does not demonstrate direct target engagement in cells, but rather uses indirect measurements of JAK and STAT phosphorylation, as well as inflammatory/disease endpoints in animal models. The relative engagement of each JAK isoform by tofacitinib is unclear in these systems (i.e., IC50 values may or may not reflect the cellular inhibition by tofacitinib). Users should consider assaying each JAK isoform (e.g., phosopho-JAK1/2/3) in their cell-based and in vivo experiments to define the specific contributions of each JAK-dependent pathway, especially if isoform-specific effects are being studied. Aug 29 2016 - 10:51am
MOA
Inhibitor
(Chemical Probes.org)
DESCRIPTION
For the treatment of moderate to severe rheumatoid arthritis which is resistant or intolerant to methotrexate therapy. It may also be used as an adjunct to methotrexate therapy, or other non-biologic disease-modifying antirheumatic drugs (DMARDS), when methotrexate alone is not sufficient. Tofacitinib has also been investigated as a preventative therapy for kidney transplant rejections, and as a treatment for psoriasis, ulcerative colitis, and ankylosing spondylitis. It is not to be initiated in patients with a history of chronic or recurrent infections, or in the presence of active infection, even if localized, due to reports of serious and sometimes fatal infections (commonly pneumonia, herpes zoster and urinary tract infections). Use of tofacitinib is also discouraged in those who have been, or are likely to be, exposed to TB. An increased likelihood of exposure may be encountered by traveling to certain areas. In addition, tofacitinib is not to be used in patients with severe hepatic impairment, or low hemoglobin (less than 9g/dL). Cautioned is advised when using tofacitinib in patients at risk of gastrointestinal perforation, and in the elderly who are more susceptible to infection.
(PKIDB)
DESCRIPTION
Potent Trk inhibitor; inhibits TrkA, TrkB and TrkC
(Tocris Bioactive Compound Library)
DESCRIPTION
Potent JAK inhibitor
(Tocriscreen Plus)
[[ p.pathway_name ]]
[[ compound.targets[tid].gene_name ]]
Cell lines
12
Organisms
2
Compound Sets
41
AdooQ Bioactive Compound Library
ChEMBL Approved Drugs
ChEMBL Drugs
Chemical Probes.org
Chemical proteomics reveals the target landscape of 1,000 kinase inhibitors
Clinical kinase drugs
CovalentInDB
CZ-OPENSCREEN Bioactive Library
Drug Repurposing Hub
DrugBank
DrugBank Approved Drugs
DrugCentral
DrugCentral Approved Drugs
DrugMAP
DrugMAP Approved Drugs
Enamine BioReference Compounds
EU-OPENSCREEN Bioactive Compound Library
EUbOPEN Chemogenomics Library
Guide to Pharmacology
High-quality chemical probes
Kinase Chemogenomic Set (KCGS 08/2017, in progress)
Kinase Chemogenomic Set (KCGS)
Kinase Inhibitors (best-in-class)
LSP-MoA library (Laboratory of Systems Pharmacology)
LSP-OptimalKinase library (Laboratory of Systems Pharmacology)
Natural product-based probes and drugs
NCATS Inxight Approved Drugs
Novartis Chemogenetic Library (NIBR MoA Box)
PKIDB
ReFrame library
Selleckchem Bioactive Compound Library
Tocris Bioactive Compound Library
Tocriscreen Plus
Tool Compound Set
Withdrawn 2.0
ZINC Tool Compounds
[[ a.name ]]
[[ ligand_id ]]
free of charge
External IDs
78
Molecular Weight
312.17
Hydrogen Bond Acceptors
5
Hydrogen Bond Donors
1
Rotatable Bonds
3
Ring Count
3
Aromatic Ring Count
2
cLogP
1.54
TPSA
88.91
Fraction CSP3
0.5
Chiral centers
2.0
Largest ring
6.0
QED
0.93
Structural alerts
0
No structural alerts detected
Related compounds
Custom attributes
(extracted from source data)
Target Type
Enzymes
Target
JAK3
Tyrosine-protein kinase JAK1
Tyrosine-protein kinase JAK2
Tyrosine-protein kinase JAK3
JAK1
JAK2
ROCK2
LCK
JAK3, JAK2, JAK1, TYK2, DCLK3
JAK1, JAK2, JAK3
JAK3 inhibitor
Bacterial
Fungal
Influenza Virus
TYK2
Apoptosis related,JAK
Anti-infection,JAK
Known off targets
JAK1, JAK2
Kinase group
TK
Pathway
Angiogenesis
Cell Cycle/Checkpoint
Cytoskeletal Signaling
Chromatin/Epigenetic
Stem Cells
JAK/STAT Signaling
Apoptosis
Epigenetics
Protein Tyrosine Kinase/RTK
Stem Cell/Wnt
Anti-infection
Primary Target
JAK Kinase
MOA
JAK
Inhibitor
Jak1 tyrosine kinase inhibitor
Jak3 tyrosine kinase inhibitor
JAK inhibitor
Member status
member
Indication
rheumatoid arthritis
ATC
L04AA29
Target class
Protein kinase
Kinase, Kinase, Kinase
Biosynthetic Origin
Nucleoside
Therapeutic Indication
Antiarthritic
Therapeutic Class
Antiinflammatory
Target subclass
TK, TK, TK
Recommended Cell Concentration
100 nM
Source data
