ritlecitinib   Click here for help

GtoPdb Ligand ID: 9559

Synonyms: compound 11 [PMID: 28139931] | example 5 [WO2015083028] | PF-06651600 | PF06651600
Immunopharmacology Ligand
Compound class: Synthetic organic
Comment: Ritlecitinib (PF-06651600) is a potent, orally active, selective covalent inhibitor of Janus kinase 3 (JAK3) [5], with anti-inflammatory activity in in vivo models [4]. It is example 5 in a Pfizer patent that provides SAR for 343 analogues [1]. There are three crystal structures available for compounds reported in [5] with JAK3, but not for compound 11 (the PDB identifiers are 5TTV, 5TTU and 5TTS). Pfizer's pipeline webpage indicates that the ritlecitinib program has been discontinued.
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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
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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
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) [5].
ATP concentration for JAK3 is 4 μM at Km and for JAK1 is 40 μM at Km, but some assays reported in [5] 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 - 5
pIC50 5.8 (IC50 1.64x10-6 M) [5]
Description: At 1 mM ATP.