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

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Ritlecitinib (DB14924)

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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

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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

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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)		••••••••••••			•••••••

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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	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 AUC_0-tau and C_max 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 C_max by 32% and increased AUC_inf 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

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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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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1,2-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.

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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
Litfulo	Capsule	50 mg	Oral	Pfizer Europe Ma Eeig	2023-09-20	Not applicable
Litfulo	Capsule	50 mg	Oral	Pfizer Europe Ma Eeig	2023-09-20	Not applicable
Litfulo	Capsule	50 mg	Oral	Pfizer Europe Ma Eeig	2023-09-20	Not applicable
Litfulo	Capsule	50 mg/1	Oral	Pfizer Laboratories Div Pfizer Inc	2023-07-06	Not applicable

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

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]

External Links

ChemSpider

59718512

BindingDB

209866

RxNav

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

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

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Details1. Tyrosine-protein kinase JAK3

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]

Details2. Tyrosine-protein kinase Tec

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]

Details3. Tyrosine-protein kinase ITK/TSK

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]

Details4. Tyrosine-protein kinase TXK

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]

Details5. Tyrosine-protein kinase BTK

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]

Details6. Cytoplasmic tyrosine-protein kinase BMX

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]

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Drug created at May 20, 2019 14:35 / Updated at December 07, 2023 08:36