PRN694   Click here for help

GtoPdb Ligand ID: 9285

Immunopharmacology Ligand
Compound class: Synthetic organic
Comment: PRN694 is a small molecule, covalent inhibitor somewhat selective for the TEC family kinases, IL-2-inducible T cell kinase (ITK) and TXK tyrosine kinase (also known as resting lymphocyte kinase or RLK) [2-3]. In vitro PRN694 is a potent inhibitor of Th1 and Th17 differentiation and cytokine production (IFN-γ production for Th1 and IL-17A for Th17), and in vivo PRN694 markedly reduces disease progression in a mouse colitis model [2]. It is suggested that dual ITK and RLK inhibition may represent a novel therapeutic model for amelioration of Th1-mediated inflammatory diseases.
Mechanistically PRN694 inhibits kinase activity by binding irreversibly to cysteine residue 442 of ITK and 350 of RLK [3]. A series of compounds including PRN694 is claimed in patent WO2014036016 [1]. Example 29 is an enantiomer of PRN694 with one unspecified stereocenter.
Click here for help
2D Structure
Click here for help
Click here for structure editor
Physico-chemical Properties
Click here for help
Hydrogen bond acceptors 6
Hydrogen bond donors 2
Rotatable bonds 12
Topological polar surface area 107.5
Molecular weight 543.25
XLogP 4.3
No. Lipinski's rules broken 0
Click here for help
Canonical SMILES C=CC(=O)N1CCCC1Cn1c(NC(=O)c2ccc(s2)C(F)F)nc2c1ccc(c2)CNC(C(C)(C)C)C
Isomeric SMILES C=CC(=O)N1CCC[C@@H]1Cn1c(NC(=O)c2ccc(s2)C(F)F)nc2c1ccc(c2)CN[C@H](C(C)(C)C)C
InChI InChI=1S/C28H35F2N5O2S/c1-6-24(36)34-13-7-8-19(34)16-35-21-10-9-18(15-31-17(2)28(3,4)5)14-20(21)32-27(35)33-26(37)23-12-11-22(38-23)25(29)30/h6,9-12,14,17,19,25,31H,1,7-8,13,15-16H2,2-5H3,(H,32,33,37)/t17-,19+/m0/s1
Bioactivity Comments
In a kinase screening panel of 250 kinases ITK, TXK, BTK and BMX (all TEC family), and CLK2, CLK4, BLK, JAK3 and YES were the only enzymes inhibited by more than 90% at 1 μm PRN694 [3].
Selectivity at enzymes
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
IL2 inducible T cell kinase Primary target of this compound Hs Inhibitor Inhibition 9.5 pIC50 - 3
pIC50 9.5 (IC50 3x10-10 M) [3]
TXK tyrosine kinase Primary target of this compound Hs Inhibitor Inhibition 8.9 pIC50 - 3
pIC50 8.9 (IC50 1.4x10-9 M) [3]
tec protein tyrosine kinase Hs Inhibitor Inhibition 8.5 pIC50 - 3
pIC50 8.5 (IC50 3.3x10-9 M) [3]
BMX non-receptor tyrosine kinase Hs Inhibitor Inhibition 7.8 pIC50 - 3
pIC50 7.8 (IC50 1.7x10-8 M) [3]
Bruton tyrosine kinase Hs Inhibitor Inhibition 7.8 pIC50 - 3
pIC50 7.8 (IC50 1.7x10-8 M) [3]
Janus kinase 3 Hs Inhibitor Inhibition 7.5 pIC50 - 3
pIC50 7.5 (IC50 3x10-8 M) [3]
BLK proto-oncogene, Src family tyrosine kinase Hs Inhibitor Inhibition 6.9 pIC50 - 3
pIC50 6.9 (IC50 1.25x10-7 M) [3]