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 rates
Build, train, & validate machine-learning models
with evidence-based and structured datasets.
See how
Build, train, & validate predictive machine-learning models with structured datasets.
See how
Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofSevere alopecia areata (aa)••••••••••••••••••••••• ••••••••••••
Treatment ofSevere alopecia areata (aa)•••••••••••••••••••
Contraindications & Blackbox Warnings
Prevent Adverse Drug Events Today
Tap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.
Learn more
Avoid life-threatening adverse drug events with our Clinical API
Learn more
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

TargetActionsOrganism
ATyrosine-protein kinase JAK3
inhibitor
Humans
ATyrosine-protein kinase Tec
inhibitor
Humans
ATyrosine-protein kinase ITK/TSK
inhibitor
Humans
ATyrosine-protein kinase TXK
inhibitor
Humans
ATyrosine-protein kinase BTK
inhibitor
Humans
ACytoplasmic tyrosine-protein kinase BMX
inhibitor
Humans
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
Improve decision support & research outcomes
With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!
See the data
Improve decision support & research outcomes with our structured adverse effects data.
See a data sample
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
Not Available

Interactions

Drug Interactions
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.
DrugInteraction
1,2-BenzodiazepineThe serum concentration of 1,2-Benzodiazepine can be increased when it is combined with Ritlecitinib.
AbametapirThe serum concentration of Ritlecitinib can be increased when it is combined with Abametapir.
AbataceptThe risk or severity of adverse effects can be increased when Abatacept is combined with Ritlecitinib.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Ritlecitinib.
AbirateroneThe 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 regions
Our datasets provide approved product information including:
dosage, form, labeller, route of administration, and marketing period.
Access now
Access drug product information from over 10 global regions.
Access now
Product Ingredients
IngredientUNIICASInChI Key
Ritlecitinib tosylateEAG4T1459K2192215-81-7YOZLVAFWYLSRRN-VZXYPILPSA-N
International/Other Brands
Litfulo (Pfizer Inc.)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
LitfuloCapsule50 mg/1OralU.S. Pharmaceuticals2023-07-06Not applicableUS flag
LitfuloCapsule50 mgOralPfizer Europe Ma Eeig2023-09-20Not applicableEU flag
LitfuloCapsule50 mgOralPfizer Europe Ma Eeig2023-09-20Not applicableEU flag
LitfuloCapsule50 mgOralPfizer Europe Ma Eeig2023-09-20Not applicableEU flag
LitfuloCapsule50 mg/1OralPfizer Laboratories Div Pfizer Inc2023-07-06Not applicableUS flag

Categories

Drug Categories
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
  1. 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]
  2. 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]
  3. 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]
  4. 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]
  5. FDA Approved Drug Products: LITFULO (ritlecitinib) capsules for oral use (June 2023) [Link]
  6. Business Wire: FDA Approves Pfizer’s LITFULO (Ritlecitinib) for Adults and Adolescents With Severe Alopecia Areata [Link]
  7. EMA Approved Drug Products: Litfulo (ritlecitinib) Oral Capsules [Link]
  8. Pfizer: European Commission Approves Pfizer’s LITFULO™ for Adolescents and Adults With Severe Alopecia Areata [Link]
  9. Health Canada Approved Drug Proucts: LITFULO (Ritlecitinib) capsule for oral use (Dec 2023) [Link]
ChemSpider
59718512
BindingDB
209866
RxNav
2641595
ChEMBL
CHEMBL4085457
ZINC
ZINC000526061581
Wikipedia
Ritlecitinib

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentAlopecia Areata (AA)1
3RecruitingTreatmentActive Nonsegmental Vitiligo / Stable Nonsegmental Vitiligo2
3RecruitingTreatmentVitiligo1
2Active Not RecruitingOtherAlopecia Areata (AA)1
2CompletedTreatmentActive Non-segmental Vitiligo1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral50 mg/1
CapsuleOral50 mg
CapsuleOral80.128 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9617258No2017-04-112034-12-03US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.457 mg/mLALOGPS
logP1.8ALOGPS
logP1.47Chemaxon
logS-2.8ALOGPS
pKa (Strongest Acidic)13.59Chemaxon
pKa (Strongest Basic)6.6Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count4Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area73.91 Å2Chemaxon
Rotatable Bond Count3Chemaxon
Refractivity82.84 m3·mol-1Chemaxon
Polarizability29.95 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-001i-0090000000-a355ec9ec587aec293b9
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-001i-1190000000-0902c7837b2502d930b5
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-001j-4090000000-cb4fe40ddb01efec9338
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-001i-0190000000-398b8f2a95bb79be5f60
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-014j-4790000000-99542b305d2cb7ac09bf
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-001l-6980000000-768e56b7f39411db0383
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
Not Available

Targets

Build, predict & validate machine-learning models
Use our structured and evidence-based datasets to unlock new
insights and accelerate drug research.
Learn more
Use our structured and evidence-based datasets to unlock new insights and accelerate drug research.
Learn more
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
  1. 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]
  2. 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]
  3. 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]
  4. 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
  1. 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]
  2. 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
  1. 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]
  2. 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
  1. 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]
  2. 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
  1. 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]
  2. 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
  1. 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]
  2. 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
Substrate
Inhibitor
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
  1. 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
  1. FDA Approved Drug Products: LITFULO (ritlecitinib) capsules for oral use (June 2023) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
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
  1. 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
  1. 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
  1. 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
  1. 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
  1. 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
  1. 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
  1. 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
  1. 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
  1. 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
  1. 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
  1. 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
  1. 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
  1. 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