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.
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2D Structure
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Physico-chemical Properties
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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
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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
1. Brameld KA, Owens TA. (2014)
Benzimidazole derivatives as itk inhibitors.
Patent number: WO2014036016. Assignee: Principia Biopharma Inc.. Priority date: 31/08/2012. Publication date: 06/03/2014.
2. Cho HS, Shin HM, Haberstock-Debic H, Xing Y, Owens TD, Funk JO, Hill RJ, Bradshaw JM, Berg LJ. (2015)
A Small Molecule Inhibitor of ITK and RLK Impairs Th1 Differentiation and Prevents Colitis Disease Progression.
J Immunol, 195 (10): 4822-31. [PMID:26466958]
3. Zhong Y, Dong S, Strattan E, Ren L, Butchar JP, Thornton K, Mishra A, Porcu P, Bradshaw JM, Bisconte A et al.. (2015)
Targeting interleukin-2-inducible T-cell kinase (ITK) and resting lymphocyte kinase (RLK) using a novel covalent inhibitor PRN694.
J Biol Chem, 290 (10): 5960-78. [PMID:25593320]