Selective JAK3 Inhibitors with a Covalent Reversible Binding Mode Targeting a New Induced Fit Binding Pocket.

Janus kinases (JAKs) are a family of cytoplasmatic tyrosine kinases that are attractive targets for the development of anti-inflammatory drugs given their roles in cytokine signaling. One question regarding JAKs and their inhibitors that remains under intensive debate is whether JAK inhibitors should be isoform selective. Since JAK3 functions are restricted to immune cells, an isoform-selective inhibitor for JAK3 could be especially valuable to achieve clinically more useful and precise effects.

Tofacitinib and analogs as inhibitors of the histone kinase PRK1 (PKN1).

Aim: The histone kinase PRK1 has been identified as a potential target to combat prostate cancer but selective PRK1 inhibitors are lacking. The US FDA -approved JAK1-3 inhibitor tofacitinib also potently inhibits PRK1 in vitro.

Results: We show that tofacitinib also inhibits PRK1 in a cellular setting.

Novel hinge-binding motifs for Janus kinase 3 inhibitors: a comprehensive structure-activity relationship study on tofacitinib bioisosteres.

The Janus kinases (JAKs) are a family of cytosolic tyrosine kinases crucially involved in cytokine signaling. JAKs have been demonstrated to be valid targets in the treatment of inflammatory and myeloproliferative disorders, and two inhibitors, tofacitinib and ruxolitinib, recently received their marketing authorization. Despite this success, selectivity within the JAK family remains a major issue.

2-(3-{(3R,4R)-4-Methyl-3-[meth-yl(7H-pyrrolo-[2,3-d]pyrimidin-4-yl)amino]-piperidin-1-yl}oxetan-3-yl)aceto-nitrile monohydrate.

In the title compound, C18H24N6O·H2O, the piperidine ring adopts a chair conformation with an N-C-C-C torsion angle of 39.5 (5)° between the cis-related substituents. The pyrrole N-H group forms a water-mediated inter-molecular hydrogen bond to one of the N atoms of the annelated pyrimidine ring.

Design and synthesis of tricyclic JAK3 inhibitors with picomolar affinities as novel molecular probes.

The Janus kinase (JAK) signaling pathway is of particular importance in the pathology of inflammatory diseases and oncological disorders, and the inhibition of Janus kinase 3 (JAK3) with small molecules has proven to provide therapeutic immunosuppression. A novel class of tricyclic JAK inhibitors derived from the 3-methyl-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine scaffold was designed based on the tofacitinib-JAK3 crystal structure by applying a rigidization approach. A convenient synthetic strategy to access the scaffold via an intramolecular Heck reaction was developed, and a small library of inhibitors was prepared and characterized using in vitro biochemical as well as cellular assays.

1-[(3RS,4RS)-1-Benzyl-4-methyl-piperi-din-3-yl]-1,6-dihydro-imidazo[4,5-d]pyrrolo-[2,3-b]pyridine hemihydrate.

The benzyl residue in the title compound, C(21)H(23)N(5)·0.5H(2)O, is oriented at a dihedral angle of 83.8 (3)° towards the 1,6-dihydro-imidazo[4,5-d]pyrrolo-[2,3-b]pyridine system.

N-[(3RS,4RS)-1-Benzyl-4-methyl-piperidin-3-yl]-5-nitro-1-phenyl-sulfonyl-1H-pyrrolo-[2,3-b]pyridine-4-amine.

The pyrrolo-pyridine system in the title compound, C(27)H(29)N(5)O(4)S, is oriented at a dihedral angle of 71.20 (5)° towards the phenyl ring of the tosyl residue and at a dihedral angle of 45.43 (4)° towards the benzyl group.

N-[(3RS,4SR)-1-Benzyl-4-methyl-piperi-din-3-yl]-1-(4-methylphenyl-sulfonyl)-5-nitro-1H-pyrrolo-[2,3-b]pyridin-4-amine.

The structure of the title compound, C(27)H(29)N(5)O(4)S, displays an intra-molecular N-H⋯O hydrogen bond. The pyrrolo-[2,3-b]pyridine core makes a dihedral angle of 85.5 (4)° with the benzyl residue and a dihedral angle of 89.