Ritlecitinib
Identification
- Summary
Ritlecitinib is a kinase inhibitor used to treat severe alopecia areata in adults and adolescents 12 years and older.
- Brand Names
- Litfulo
- Generic Name
- Ritlecitinib
- DrugBank Accession Number
- DB14924
- Background
Ritlecitinib (PF-06651600) is a highly selective inhibitor of Janus kinase 3 (JAK3) and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase family. In June 2023, it was approved by the FDA for the treatment of severe alopecia areata in adults and adolescents 12 years and older.5,6 It was further approved by the EMA in September 2023.8 Ritlecitinib is administered orally and is the first member of its class.1,2
Ritlecitinib binds covalently to Cys-909 of JAK3, a site where other JAK isoforms have a serine residue. This makes ritlecitinib a highly selective and irreversible JAK3 inhibitor.1,2 Other kinases have a cysteine at a position equivalent to Cys-909 in JAK3, and several of them belong to the TEC kinase family. It has been suggested that the dual activity of ritlecitinib toward JAK3 and the TEC kinase family block cytokine signaling as well as the cytolytic activity of T cells, both implicated in the pathogenesis of alopecia areata.1
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
- Weight
- Average: 285.351
Monoisotopic: 285.158960252 - Chemical Formula
- C15H19N5O
- Synonyms
- 2-propen-1-one, 1-((2S,5R)-2-methyl-5-(7H-pyrrolo(2,3-D)pyrimidin-4-ylamino)-1-piperidinyl)-
- External IDs
- PF-06651600
Pharmacology
- Indication
Ritlecitinib is indicated for the treatment of severe alopecia areata in adults and adolescents 12 years and older. It is not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, cyclosporine or other potent immunosuppressants.5,7
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Severe alopecia areata (aa) •••••••••••• ••••••••••• ••••• ••••••• Treatment of Severe alopecia areata (aa) •••••••••••• ••••••• - Contraindications & Blackbox Warnings
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- Pharmacodynamics
Ritlecitinib is a kinase inhibitor that promotes the decrease of absolute lymphocyte levels, T lymphocytes (CD3) and T lymphocyte subsets (CD4 and CD8) in a dose-dependent manner. Ritlecitinib also promotes a decrease in NK cells (CD16/56), which remain stable up to week 48 after initiating treatment. In patients treated with 50 mg of ritlecitinib once a day, the decrease in median lymphocyte levels remains consistent up to week 48.5
At 12 times the mean maximum exposure of the 50 mg dose given to patients with alopecia areata once a day, ritlecitinib did not cause a clinically relevant effect on the QTc interval.[] The use of ritlecitinib is associated with the development of serious infections, malignancies (including non-melanoma skin cancer), major adverse cardiovascular events, thromboembolic events, and hypersensitivity. In the postmarketing safety study of another JAK inhibitor in patients with rheumatoid arthritis over 50 years of age with at least one cardiovascular risk factor, JAK inhibitors were associated with a higher rate of all-cause mortality, including sudden cardiovascular death, compared to TNF blockers.5
- Mechanism of action
Alopecia areata is an autoimmune disorder that causes hair loss mainly in the scalp but also on the face and other areas. In normal conditions, hair follicles are immune-privileged sites characterized by the presence of well-suppressed natural killer cells. However, disruptions to this system can lead to the loss of immune privilege and cause alopecia areata. Genome-wide association studies have linked the overexpression of UL16-binding protein 3 (ULBP3), a protein that binds to natural killer cell receptors, to the pathogenesis of alopecia areata. The overexpression of ULBP3 promotes the attack of cytotoxic cluster of differentiation 8-positive (CD8+) NK group 2D-positive (NKG2D+) T cells to hair follicles, leading to hair follicle dystrophy. CD8+ NKG2D+ T cells promote the inflammation of hair follicles through interferon-γ (IFN-γ) and interleukin-15 (IL-15) signaling pathways, which consequently activate Janus kinase (JAK)/signal transducer and activator of transcription (STAT) molecular pathways. Therefore, JAK inhibitors have been proposed for the treatment of alopecia areata.3,4
Ritlecitinib inhibits Janus kinase 3 (JAK3) and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase family in an irreversible manner by blocking the adenosine triphosphate (ATP) binding site. In vitro, ritlecitinib inhibits cytokine-induced STAT phosphorylation mediated by JAK3-dependent receptors and the signaling of immune receptors dependent on TEC kinase family members.5 Although it is possible that JAK inhibitors, such as ritlecitinib, inhibit the inflammatory pathways activated in alopecia areata, the precise mechanism of action has not been fully elucidated.3,5
Target Actions Organism ATyrosine-protein kinase JAK3 inhibitorHumans ATyrosine-protein kinase Tec inhibitorHumans ATyrosine-protein kinase ITK/TSK inhibitorHumans ATyrosine-protein kinase TXK inhibitorHumans ATyrosine-protein kinase BTK inhibitorHumans ACytoplasmic tyrosine-protein kinase BMX inhibitorHumans - Absorption
Up to 200 mg, the AUC0-tau and Cmax of ritlecitinib increase in an approximately dose-proportional manner, and steady state is reached approximately by day 4. Ritlecitinib has an absolute oral bioavailability of approximately 64%, and 1 hour after an oral dose is administered, peak plasma concentrations are achieved. Food does not have a clinically significant impact on the systemic exposures of ritlecitinib. The co-administration of a high-fat meal and a 100 mg ritlecitinib capsule reduced Cmax by 32% and increased AUCinf by 11%. Ritlecitinib was administered without regard to meals during clinical trials.5
- Volume of distribution
Ritlecitinib is predicted to have a volume of distribution of 1.3 L/kg.2
- Protein binding
Ritlecitinib is 14% bound to plasma proteins.5
- Metabolism
Ritlecitinib is metabolized by cytochrome P450 (CYP) and glutathione-S-transferase (GST) enzymes. The GST enzymes participating in the metabolism of ritlecitinib include cytosolic GST A1/3, M1/3/5, P1, S1, T2, Z1 and microsomal GST 1/2/3, and the CYP enzymes participating in this process include CYP3A, CYP2C8, CYP1A2, and CYP2C9. No single route contributes to more than 25% of the total metabolism of ritlecitinib.5
- Route of elimination
Ritlecitinib is mainly excreted through urine and feces. Approximately 66% and 20% of radiolabeled ritlecitinib are excreted in the urine and feces, respectively. Approximately 4% of the ritlecitinib dose is excreted unchanged drug in urine.5
- Half-life
Ritlecitinib has a terminal half-life that ranges from 1.3 to 2.3 hours.5
- Clearance
Ritlecitinib is predicted to have a blood clearance of 5.6 mL/min/kg.2
- Adverse Effects
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- Toxicity
During clinical trials, the highest single dose of ritlecitinib was 800 mg. No specific toxicities were identified at this dose, and the adverse reactions detected were comparable to those seen at lower doses. Pharmacokinetic studies indicate that in healthy adult volunteers given a single oral dose of 800 mg, more than 90% of ritlecitinib is expected to be eliminated within 48 hours. There is no specific antidote for overdose with ritlecitinib. In patients experiencing a ritlecitinib overdose, provide symptomatic and supportive treatment, and monitor for signs and symptoms of adverse reactions.5
In rats given 100 mg/kg/day of ritlecitinib (29 times the maximum recommended human dose based on AUC comparison), females had an increased incidence of combined benign and malignant thymomas, while males had a higher incidence of thyroid follicular adenomas and combined follicular adenomas and carcinomas. Ritlecitinib was negative in the bacterial reverse mutation assay and positive in an in vitro micronucleus assay in TK6 cells; however, mechanistic studies suggest that ritlecitinib is aneugenic and does not present a clinically relevant genotoxic concern.5
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your software1,2-Benzodiazepine The serum concentration of 1,2-Benzodiazepine can be increased when it is combined with Ritlecitinib. Abametapir The serum concentration of Ritlecitinib can be increased when it is combined with Abametapir. Abatacept The risk or severity of adverse effects can be increased when Abatacept is combined with Ritlecitinib. Abemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Ritlecitinib. Abiraterone The serum concentration of Abiraterone can be increased when it is combined with Ritlecitinib. - Food Interactions
- Take with or without food. The coadministration of ritlecitinib and a high-fat meal reduced the Cmax and AUC; however, food does not have a clinically significant impact on the systemic exposures of ritlecitinib.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Product Ingredients
Ingredient UNII CAS InChI Key Ritlecitinib tosylate EAG4T1459K 2192215-81-7 YOZLVAFWYLSRRN-VZXYPILPSA-N - International/Other Brands
- Litfulo (Pfizer Inc.)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Litfulo Capsule 50 mg/1 Oral U.S. Pharmaceuticals 2023-07-06 Not applicable US Litfulo Capsule 50 mg Oral Pfizer Europe Ma Eeig 2023-09-20 Not applicable EU Litfulo Capsule 50 mg Oral Pfizer Europe Ma Eeig 2023-09-20 Not applicable EU Litfulo Capsule 50 mg Oral Pfizer Europe Ma Eeig 2023-09-20 Not applicable EU Litfulo Capsule 50 mg/1 Oral Pfizer Laboratories Div Pfizer Inc 2023-07-06 Not applicable US
Categories
- Drug Categories
- Cytochrome P-450 CYP1A2 Inhibitors
- Cytochrome P-450 CYP1A2 Inhibitors (strength unknown)
- Cytochrome P-450 CYP1A2 Substrates
- Cytochrome P-450 CYP2C8 Substrates
- Cytochrome P-450 CYP2C9 Substrates
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Inhibitors
- Cytochrome P-450 CYP3A4 Inhibitors (strength unknown)
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Substrates
- Immunomodulatory Agents
- Immunosuppressive Agents
- Janus Kinase 3, antagonists & inhibitors
- Janus Kinase Inhibitors
- Janus Kinases, antagonists & inhibitors
- Classification
- Not classified
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 2OYE00PC25
- CAS number
- 1792180-81-4
- InChI Key
- CBRJPFGIXUFMTM-WDEREUQCSA-N
- InChI
- InChI=1S/C15H19N5O/c1-3-13(21)20-8-11(5-4-10(20)2)19-15-12-6-7-16-14(12)17-9-18-15/h3,6-7,9-11H,1,4-5,8H2,2H3,(H2,16,17,18,19)/t10-,11+/m0/s1
- IUPAC Name
- 1-[(2S,5R)-2-methyl-5-({7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)piperidin-1-yl]prop-2-en-1-one
- SMILES
- C[C@H]1CC[C@H](CN1C(=O)C=C)NC1=NC=NC2=C1C=CN2
References
- Synthesis Reference
Thorarensen, A., et al. (2023). Pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyrazinyl and pyrrolo[2,3-d]pyridinyl acrylamides (U.S. Patent No. 2023/0009153 A1). U.S. Patent and Trademark Office. https://patentimages.storage.googleapis.com/fb/75/3e/68ad4603d518f9/US20230009153A1.pdf
- General References
- Ramirez-Marin HA, Tosti A: Evaluating the Therapeutic Potential of Ritlecitinib for the Treatment of Alopecia Areata. Drug Des Devel Ther. 2022 Feb 17;16:363-374. doi: 10.2147/DDDT.S334727. eCollection 2022. [Article]
- Telliez JB, Dowty ME, Wang L, Jussif J, Lin T, Li L, Moy E, Balbo P, Li W, Zhao Y, Crouse K, Dickinson C, Symanowicz P, Hegen M, Banker ME, Vincent F, Unwalla R, Liang S, Gilbert AM, Brown MF, Hayward M, Montgomery J, Yang X, Bauman J, Trujillo JI, Casimiro-Garcia A, Vajdos FF, Leung L, Geoghegan KF, Quazi A, Xuan D, Jones L, Hett E, Wright K, Clark JD, Thorarensen A: Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition. ACS Chem Biol. 2016 Dec 16;11(12):3442-3451. doi: 10.1021/acschembio.6b00677. Epub 2016 Nov 10. [Article]
- Yan D, Fan H, Chen M, Xia L, Wang S, Dong W, Wang Q, Niu S, Rao H, Chen L, Nie X, Fang Y: The efficacy and safety of JAK inhibitors for alopecia areata: A systematic review and meta-analysis of prospective studies. Front Pharmacol. 2022 Aug 24;13:950450. doi: 10.3389/fphar.2022.950450. eCollection 2022. [Article]
- Triyangkulsri K, Suchonwanit P: Role of janus kinase inhibitors in the treatment of alopecia areata. Drug Des Devel Ther. 2018 Jul 27;12:2323-2335. doi: 10.2147/DDDT.S172638. eCollection 2018. [Article]
- FDA Approved Drug Products: LITFULO (ritlecitinib) capsules for oral use (June 2023) [Link]
- Business Wire: FDA Approves Pfizer’s LITFULO (Ritlecitinib) for Adults and Adolescents With Severe Alopecia Areata [Link]
- EMA Approved Drug Products: Litfulo (ritlecitinib) Oral Capsules [Link]
- Pfizer: European Commission Approves Pfizer’s LITFULO™ for Adolescents and Adults With Severe Alopecia Areata [Link]
- Health Canada Approved Drug Proucts: LITFULO (Ritlecitinib) capsule for oral use (Dec 2023) [Link]
- External Links
- ChemSpider
- 59718512
- BindingDB
- 209866
- 2641595
- ChEMBL
- CHEMBL4085457
- ZINC
- ZINC000526061581
- Wikipedia
- Ritlecitinib
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 3 Active Not Recruiting Treatment Alopecia Areata (AA) 1 3 Recruiting Treatment Active Nonsegmental Vitiligo / Stable Nonsegmental Vitiligo 2 3 Recruiting Treatment Vitiligo 1 2 Active Not Recruiting Other Alopecia Areata (AA) 1 2 Completed Treatment Active Non-segmental Vitiligo 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Capsule Oral 50 mg/1 Capsule Oral 50 mg Capsule Oral 80.128 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US9617258 No 2017-04-11 2034-12-03 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.457 mg/mL ALOGPS logP 1.8 ALOGPS logP 1.47 Chemaxon logS -2.8 ALOGPS pKa (Strongest Acidic) 13.59 Chemaxon pKa (Strongest Basic) 6.6 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 4 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 73.91 Å2 Chemaxon Rotatable Bond Count 3 Chemaxon Refractivity 82.84 m3·mol-1 Chemaxon Polarizability 29.95 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-001i-0090000000-a355ec9ec587aec293b9 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-001i-1190000000-0902c7837b2502d930b5 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-001j-4090000000-cb4fe40ddb01efec9338 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-001i-0190000000-398b8f2a95bb79be5f60 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-014j-4790000000-99542b305d2cb7ac09bf Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-001l-6980000000-768e56b7f39411db0383 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Not Available
Targets
![](https://go.drugbank.com/assets/locked/DrugTargets2-682eb846d210ae4bf33ca03febccfb57bb1c61318e699b729e5df4dfab2c5b67.png)
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Protein tyrosine kinase activity
- Specific Function
- Non-receptor tyrosine kinase involved in various processes such as cell growth, development, or differentiation. Mediates essential signaling events in both innate and adaptive immunity and plays a...
- Gene Name
- JAK3
- Uniprot ID
- P52333
- Uniprot Name
- Tyrosine-protein kinase JAK3
- Molecular Weight
- 125097.565 Da
References
- Yan D, Fan H, Chen M, Xia L, Wang S, Dong W, Wang Q, Niu S, Rao H, Chen L, Nie X, Fang Y: The efficacy and safety of JAK inhibitors for alopecia areata: A systematic review and meta-analysis of prospective studies. Front Pharmacol. 2022 Aug 24;13:950450. doi: 10.3389/fphar.2022.950450. eCollection 2022. [Article]
- Ramirez-Marin HA, Tosti A: Evaluating the Therapeutic Potential of Ritlecitinib for the Treatment of Alopecia Areata. Drug Des Devel Ther. 2022 Feb 17;16:363-374. doi: 10.2147/DDDT.S334727. eCollection 2022. [Article]
- Telliez JB, Dowty ME, Wang L, Jussif J, Lin T, Li L, Moy E, Balbo P, Li W, Zhao Y, Crouse K, Dickinson C, Symanowicz P, Hegen M, Banker ME, Vincent F, Unwalla R, Liang S, Gilbert AM, Brown MF, Hayward M, Montgomery J, Yang X, Bauman J, Trujillo JI, Casimiro-Garcia A, Vajdos FF, Leung L, Geoghegan KF, Quazi A, Xuan D, Jones L, Hett E, Wright K, Clark JD, Thorarensen A: Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition. ACS Chem Biol. 2016 Dec 16;11(12):3442-3451. doi: 10.1021/acschembio.6b00677. Epub 2016 Nov 10. [Article]
- FDA Approved Drug Products: LITFULO (ritlecitinib) capsules for oral use (June 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Non-receptor tyrosine kinase that contributes to signaling from many receptors and participates as a signal transducer in multiple downstream pathways, including regulation of the actin cytoskeleton. Plays a redundant role to ITK in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. Required for TCR-dependent IL2 gene induction. Phosphorylates DOK1, one CD28-specific substrate, and contributes to CD28-signaling. Mediates signals that negatively regulate IL2RA expression induced by TCR cross-linking. Plays a redundant role to BTK in BCR-signaling for B-cell development and activation, especially by phosphorylating STAP1, a BCR-signaling protein. Required in mast cells for efficient cytokine production. Involved in both growth and differentiation mechanisms of myeloid cells through activation by the granulocyte colony-stimulating factor CSF3, a critical cytokine to promoting the growth, differentiation, and functional activation of myeloid cells. Participates in platelet signaling downstream of integrin activation. Cooperates with JAK2 through reciprocal phosphorylation to mediate cytokine-driven activation of FOS transcription. GRB10, a negative modifier of the FOS activation pathway, is another substrate of TEC. TEC is involved in G protein-coupled receptor- and integrin-mediated signalings in blood platelets. Plays a role in hepatocyte proliferation and liver regeneration and is involved in HGF-induced ERK signaling pathway. TEC regulates also FGF2 unconventional secretion (endoplasmic reticulum (ER)/Golgi-independent mechanism) under various physiological conditions through phosphorylation of FGF2 'Tyr-215'. May also be involved in the regulation of osteoclast differentiation.
- Specific Function
- Atp binding
- Gene Name
- TEC
- Uniprot ID
- P42680
- Uniprot Name
- Tyrosine-protein kinase Tec
- Molecular Weight
- 73580.73 Da
References
- Ramirez-Marin HA, Tosti A: Evaluating the Therapeutic Potential of Ritlecitinib for the Treatment of Alopecia Areata. Drug Des Devel Ther. 2022 Feb 17;16:363-374. doi: 10.2147/DDDT.S334727. eCollection 2022. [Article]
- FDA Approved Drug Products: LITFULO (ritlecitinib) capsules for oral use (June 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Non-membrane spanning protein tyrosine kinase activity
- Specific Function
- Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-c...
- Gene Name
- ITK
- Uniprot ID
- Q08881
- Uniprot Name
- Tyrosine-protein kinase ITK/TSK
- Molecular Weight
- 71830.405 Da
References
- Ramirez-Marin HA, Tosti A: Evaluating the Therapeutic Potential of Ritlecitinib for the Treatment of Alopecia Areata. Drug Des Devel Ther. 2022 Feb 17;16:363-374. doi: 10.2147/DDDT.S334727. eCollection 2022. [Article]
- Telliez JB, Dowty ME, Wang L, Jussif J, Lin T, Li L, Moy E, Balbo P, Li W, Zhao Y, Crouse K, Dickinson C, Symanowicz P, Hegen M, Banker ME, Vincent F, Unwalla R, Liang S, Gilbert AM, Brown MF, Hayward M, Montgomery J, Yang X, Bauman J, Trujillo JI, Casimiro-Garcia A, Vajdos FF, Leung L, Geoghegan KF, Quazi A, Xuan D, Jones L, Hett E, Wright K, Clark JD, Thorarensen A: Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition. ACS Chem Biol. 2016 Dec 16;11(12):3442-3451. doi: 10.1021/acschembio.6b00677. Epub 2016 Nov 10. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Non-receptor tyrosine kinase that plays a redundant role with ITK in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. When antigen presenting cells (APC) activate T-cell receptor (TCR), a series of phosphorylation lead to the recruitment of TXK to the cell membrane, where it is phosphorylated at Tyr-420. Phosphorylation leads to TXK full activation. Contributes also to signaling from many receptors and participates in multiple downstream pathways, including regulation of the actin cytoskeleton. Like ITK, can phosphorylate PLCG1, leading to its localization in lipid rafts and activation, followed by subsequent cleavage of its substrates. In turn, the endoplasmic reticulum releases calcium in the cytoplasm and the nuclear activator of activated T-cells (NFAT) translocates into the nucleus to perform its transcriptional duty. With PARP1 and EEF1A1, TXK forms a complex that acts as a T-helper 1 (Th1) cell-specific transcription factor and binds the promoter of IFNG to directly regulate its transcription, and is thus involved importantly in Th1 cytokine production. Phosphorylates both PARP1 and EEF1A1. Phosphorylates also key sites in LCP2 leading to the up-regulation of Th1 preferred cytokine IL-2. Phosphorylates 'Tyr-201' of CTLA4 which leads to the association of PI-3 kinase with the CTLA4 receptor.
- Specific Function
- Atp binding
- Gene Name
- TXK
- Uniprot ID
- P42681
- Uniprot Name
- Tyrosine-protein kinase TXK
- Molecular Weight
- 61257.9 Da
References
- Ramirez-Marin HA, Tosti A: Evaluating the Therapeutic Potential of Ritlecitinib for the Treatment of Alopecia Areata. Drug Des Devel Ther. 2022 Feb 17;16:363-374. doi: 10.2147/DDDT.S334727. eCollection 2022. [Article]
- Telliez JB, Dowty ME, Wang L, Jussif J, Lin T, Li L, Moy E, Balbo P, Li W, Zhao Y, Crouse K, Dickinson C, Symanowicz P, Hegen M, Banker ME, Vincent F, Unwalla R, Liang S, Gilbert AM, Brown MF, Hayward M, Montgomery J, Yang X, Bauman J, Trujillo JI, Casimiro-Garcia A, Vajdos FF, Leung L, Geoghegan KF, Quazi A, Xuan D, Jones L, Hett E, Wright K, Clark JD, Thorarensen A: Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition. ACS Chem Biol. 2016 Dec 16;11(12):3442-3451. doi: 10.1021/acschembio.6b00677. Epub 2016 Nov 10. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Protein tyrosine kinase activity
- Specific Function
- Non-receptor tyrosine kinase indispensable for B lymphocyte development, differentiation and signaling. Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately le...
- Gene Name
- BTK
- Uniprot ID
- Q06187
- Uniprot Name
- Tyrosine-protein kinase BTK
- Molecular Weight
- 76280.71 Da
References
- Ramirez-Marin HA, Tosti A: Evaluating the Therapeutic Potential of Ritlecitinib for the Treatment of Alopecia Areata. Drug Des Devel Ther. 2022 Feb 17;16:363-374. doi: 10.2147/DDDT.S334727. eCollection 2022. [Article]
- Telliez JB, Dowty ME, Wang L, Jussif J, Lin T, Li L, Moy E, Balbo P, Li W, Zhao Y, Crouse K, Dickinson C, Symanowicz P, Hegen M, Banker ME, Vincent F, Unwalla R, Liang S, Gilbert AM, Brown MF, Hayward M, Montgomery J, Yang X, Bauman J, Trujillo JI, Casimiro-Garcia A, Vajdos FF, Leung L, Geoghegan KF, Quazi A, Xuan D, Jones L, Hett E, Wright K, Clark JD, Thorarensen A: Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition. ACS Chem Biol. 2016 Dec 16;11(12):3442-3451. doi: 10.1021/acschembio.6b00677. Epub 2016 Nov 10. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Non-receptor tyrosine kinase that plays central but diverse modulatory roles in various signaling processes involved in the regulation of actin reorganization, cell migration, cell proliferation and survival, cell adhesion, and apoptosis. Participates in signal transduction stimulated by growth factor receptors, cytokine receptors, G-protein coupled receptors, antigen receptors and integrins. Induces tyrosine phosphorylation of BCAR1 in response to integrin regulation. Activation of BMX by integrins is mediated by PTK2/FAK1, a key mediator of integrin signaling events leading to the regulation of actin cytoskeleton and cell motility. Plays a critical role in TNF-induced angiogenesis, and implicated in the signaling of TEK and FLT1 receptors, 2 important receptor families essential for angiogenesis. Required for the phosphorylation and activation of STAT3, a transcription factor involved in cell differentiation. Also involved in interleukin-6 (IL6) induced differentiation. Plays also a role in programming adaptive cytoprotection against extracellular stress in different cell systems, salivary epithelial cells, brain endothelial cells, and dermal fibroblasts. May be involved in regulation of endocytosis through its interaction with an endosomal protein RUFY1. May also play a role in the growth and differentiation of hematopoietic cells; as well as in signal transduction in endocardial and arterial endothelial cells.
- Specific Function
- Atp binding
- Gene Name
- BMX
- Uniprot ID
- P51813
- Uniprot Name
- Cytoplasmic tyrosine-protein kinase BMX
- Molecular Weight
- 78010.17 Da
References
- Ramirez-Marin HA, Tosti A: Evaluating the Therapeutic Potential of Ritlecitinib for the Treatment of Alopecia Areata. Drug Des Devel Ther. 2022 Feb 17;16:363-374. doi: 10.2147/DDDT.S334727. eCollection 2022. [Article]
- Telliez JB, Dowty ME, Wang L, Jussif J, Lin T, Li L, Moy E, Balbo P, Li W, Zhao Y, Crouse K, Dickinson C, Symanowicz P, Hegen M, Banker ME, Vincent F, Unwalla R, Liang S, Gilbert AM, Brown MF, Hayward M, Montgomery J, Yang X, Bauman J, Trujillo JI, Casimiro-Garcia A, Vajdos FF, Leung L, Geoghegan KF, Quazi A, Xuan D, Jones L, Hett E, Wright K, Clark JD, Thorarensen A: Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition. ACS Chem Biol. 2016 Dec 16;11(12):3442-3451. doi: 10.1021/acschembio.6b00677. Epub 2016 Nov 10. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- General Function
- Vitamin d3 25-hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- FDA Approved Drug Products: LITFULO (ritlecitinib) capsules for oral use (June 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Steroid hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- Gene Name
- CYP2C8
- Uniprot ID
- P10632
- Uniprot Name
- Cytochrome P450 2C8
- Molecular Weight
- 55824.275 Da
References
- FDA Approved Drug Products: LITFULO (ritlecitinib) capsules for oral use (June 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- General Function
- Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- Gene Name
- CYP1A2
- Uniprot ID
- P05177
- Uniprot Name
- Cytochrome P450 1A2
- Molecular Weight
- 58293.76 Da
References
- FDA Approved Drug Products: LITFULO (ritlecitinib) capsules for oral use (June 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Steroid hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- Gene Name
- CYP2C9
- Uniprot ID
- P11712
- Uniprot Name
- Cytochrome P450 2C9
- Molecular Weight
- 55627.365 Da
References
- FDA Approved Drug Products: LITFULO (ritlecitinib) capsules for oral use (June 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Glutathione transferase activity
- Specific Function
- Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles.
- Gene Name
- GSTA1
- Uniprot ID
- P08263
- Uniprot Name
- Glutathione S-transferase A1
- Molecular Weight
- 25630.785 Da
References
- FDA Approved Drug Products: LITFULO (ritlecitinib) capsules for oral use (June 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Glutathione transferase activity
- Specific Function
- Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Catalyzes isomerization reactions that contribute to the biosynthesis of steroid hormones....
- Gene Name
- GSTA3
- Uniprot ID
- Q16772
- Uniprot Name
- Glutathione S-transferase A3
- Molecular Weight
- 25301.355 Da
References
- FDA Approved Drug Products: LITFULO (ritlecitinib) capsules for oral use (June 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- General Function
- Protein homodimerization activity
- Specific Function
- Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles.
- Gene Name
- GSTM1
- Uniprot ID
- P09488
- Uniprot Name
- Glutathione S-transferase Mu 1
- Molecular Weight
- 25711.555 Da
References
- FDA Approved Drug Products: LITFULO (ritlecitinib) capsules for oral use (June 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Protein homodimerization activity
- Specific Function
- Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. May govern uptake and detoxification of both endogenous compounds and xenobiotics at the t...
- Gene Name
- GSTM3
- Uniprot ID
- P21266
- Uniprot Name
- Glutathione S-transferase Mu 3
- Molecular Weight
- 26559.32 Da
References
- FDA Approved Drug Products: LITFULO (ritlecitinib) capsules for oral use (June 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Glutathione transferase activity
- Specific Function
- Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles.
- Gene Name
- GSTM5
- Uniprot ID
- P46439
- Uniprot Name
- Glutathione S-transferase Mu 5
- Molecular Weight
- 25674.455 Da
References
- FDA Approved Drug Products: LITFULO (ritlecitinib) capsules for oral use (June 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- S-nitrosoglutathione binding
- Specific Function
- Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Regulates negatively CDK5 activity via p25/p35 translocation to prevent neurodegeneration.
- Gene Name
- GSTP1
- Uniprot ID
- P09211
- Uniprot Name
- Glutathione S-transferase P
- Molecular Weight
- 23355.625 Da
References
- FDA Approved Drug Products: LITFULO (ritlecitinib) capsules for oral use (June 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Glutathione transferase activity
- Specific Function
- Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Has a sulfatase activity.
- Gene Name
- GSTT2
- Uniprot ID
- P0CG29
- Uniprot Name
- Glutathione S-transferase theta-2
- Molecular Weight
- 27505.775 Da
References
- FDA Approved Drug Products: LITFULO (ritlecitinib) capsules for oral use (June 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Protein homodimerization activity
- Specific Function
- Bifunctional enzyme showing minimal glutathione-conjugating activity with ethacrynic acid and 7-chloro-4-nitrobenz-2-oxa-1,3-diazole and maleylacetoacetate isomerase activity. Has also low glutathi...
- Gene Name
- GSTZ1
- Uniprot ID
- O43708
- Uniprot Name
- Maleylacetoacetate isomerase
- Molecular Weight
- 24212.005 Da
References
- FDA Approved Drug Products: LITFULO (ritlecitinib) capsules for oral use (June 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Glutathione transferase activity
- Specific Function
- Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Has a wide substrate specificity.
- Gene Name
- MGST1
- Uniprot ID
- P10620
- Uniprot Name
- Microsomal glutathione S-transferase 1
- Molecular Weight
- 17598.45 Da
References
- FDA Approved Drug Products: LITFULO (ritlecitinib) capsules for oral use (June 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Leukotriene-c4 synthase activity
- Specific Function
- Can catalyze the production of LTC4 from LTA4 and reduced glutathione. Can catalyze the conjugation of 1-chloro-2,4-dinitrobenzene with reduced glutathione.
- Gene Name
- MGST2
- Uniprot ID
- Q99735
- Uniprot Name
- Microsomal glutathione S-transferase 2
- Molecular Weight
- 16620.4 Da
References
- FDA Approved Drug Products: LITFULO (ritlecitinib) capsules for oral use (June 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Peroxidase activity
- Specific Function
- Also functions as a glutathione peroxidase.
- Gene Name
- MGST3
- Uniprot ID
- O14880
- Uniprot Name
- Microsomal glutathione S-transferase 3
- Molecular Weight
- 16516.185 Da
References
- FDA Approved Drug Products: LITFULO (ritlecitinib) capsules for oral use (June 2023) [Link]
Drug created at May 20, 2019 14:35 / Updated at December 07, 2023 08:36