ritlecitinib   Click here for help

GtoPdb Ligand ID: 9559

Synonyms: compound 11 [PMID: 28139931] | example 5 [WO2015083028] | Litfulo® | PF-06651600 | PF06651600
Approved drug Immunopharmacology Ligand
ritlecitinib is an approved drug (FDA, UK & EMA (2023))
Compound class: Synthetic organic
Comment: Ritlecitinib (PF-06651600) is a potent, orally active, molecule with dual inhibitor activities. It acts as a covalent and selective inhibitor of Janus kinase 3 (JAK3) [7] (a type I inhibitor, that binds to the kinase in its ATP pocket), and it also inhibits TEC family kinases (BTK, ITK, TEC, Etk, TXK) that are involved in immune cell regulation. It has demonstrated anti-inflammatory activities in in vivo models [6]. Ritlecitinib is example 5 in a Pfizer patent that provides SAR for 343 analogues [1]. There are three crystal structures available for compounds reported in [7] with JAK3, but not for compound 11 (the PDB identifiers are 5TTV, 5TTU and 5TTS).
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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View interactive charts of activity data across species
2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/). All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 5
Hydrogen bond donors 2
Rotatable bonds 4
Topological polar surface area 73.91
Molecular weight 285.16
XLogP 1.92
No. Lipinski's rules broken 0

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)

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Canonical SMILES C=CC(=O)N1CC(CCC1C)Nc1ncnc2c1cc[nH]2
Isomeric SMILES C=CC(=O)N1C[C@@H](CC[C@@H]1C)Nc1ncnc2c1cc[nH]2
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
InChI Key CBRJPFGIXUFMTM-WDEREUQCSA-N

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
Immunopharmacology Comments
PF-06651600 is a JAK3 inhibitor with potential clinical utility as a therapeutic option for autoimmune diseases.
Inhibition of JAK3 modulates γ-common chain cytokine pathways (e.g., IL-7, IL-9, IL-15, and IL-21) that are drivers of ulcerative colitis pathophysiology. However, unlike JAK1 inhibitors, JAK3 inhibition does not disrupt the actions of immunoregulatory cytokines (e.g., IL-10, IL-27, and IL-21) which are critical regulators of immune homeostasis in the digestive tract. Ritlecitinib-mediated inhibition of TEC family kinases impedes the functions of cytotoxic immune cells (CD8+ T cell, natural killer cells) that are involved in the pathogenesis of inflammatory bowel disease.
Immunopharmacology Disease
Disease X-Refs Comment References
Ulcerative colitis Disease Ontology: DOID:8577
OMIM: 266600
Orphanet: ORPHA771
 Phase 2 clinical candidate for UC (NCT02958865).
Crohn's disease Disease Ontology: DOID:8778
OMIM: 266600
Orphanet: ORPHA206
 Phase 2 clinical candidate for patients with moderate to severe CD (NCT03395184).
Alopecia areata Disease Ontology: DOID:986
 Phase 2b/3 clinical candidate for AA (NCT03732807). In August 2021, Pfizer announced that ritlecitinib had met its primary endpoint (reduction in hair loss) in this study. Results from phase 2a NCT02974868 comparing ritlecitinib and brepocitinib with placebo at 24 weeks were published by King et al. (2021). 2
Rheumatoid arthritis Disease Ontology: DOID:7148
OMIM: 180300
 Phase 2 clinical candidate for RA (NCT02969044). In this study oral treatment with ritlecitinib (200 mg once daily) was well tolerated, and was associated with significant improvements in RA disease activit.y 4