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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2D Structure
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Physico-chemical Properties
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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
SMILES / InChI / InChIKey
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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
Bioactivity Comments
PF-06651600 exhibits favourable selectivity against a screening panel of 305 kinases in vitro, and shows measurable inhibition of 7 of the 10 other kinases which share a cysteine residue analogous to Cys-909 in the JAK3 ATP binding site (these were BMX, ITK, TXK, TEC, BTK, BLK and HER4) [7].
ATP concentration for JAK3 is 4 μM at Km and for JAK1 is 40 μM at Km, but some assays reported in [7] were carried out at 1 mM ATP .
Selectivity at enzymes
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
Janus kinase 3 Primary target of this compound Hs Inhibitor Inhibition 9.5 pIC50 -
pIC50 9.5 (IC50 3x10-10 M)
Description: At 4 μM ATP (Km).
Janus kinase 1 Hs Inhibitor Inhibition 5.8 pIC50 - 7
pIC50 5.8 (IC50 1.64x10-6 M) [7]
Description: At 1 mM ATP.