TY - JOUR KW - Protein Structure, Secondary KW - Humans KW - Molecular Docking Simulation KW - Protein Binding KW - Binding Sites KW - Protein Structure, Tertiary KW - Protein-Tyrosine Kinases KW - Protein Kinase Inhibitors KW - Drug Evaluation, Preclinical KW - Intracellular Signaling Peptides and Proteins KW - ZAP-70 Protein-Tyrosine Kinase AU - H. Zhao AU - A. Caflisch AB -

The non-receptor tyrosine kinase Syk (spleen tyrosine kinase) is a pharmaceutical relevant target because its over-activation is observed in several autoimmune diseases, allergy, and asthma. Here we report the identification of two novel inhibitors of Syk by high-throughput docking into a rare C-helix-out conformation published recently. Interestingly, both compounds are slightly more active on ZAP70 (Zeta-chain-associated protein kinase 70), which is the kinase closest to Syk in the phylogenetic tree of human kinases. Taken together, the docking pose and experimental results suggest that the higher affinity of the inhibitors for ZAP70 than Syk originates from a more populated C-helix-out conformation in ZAP70. The latter observation is congruent with the 100-fold lower intrinsic activity of ZAP70 than Syk, as the C-helix-out conformation is inactive. The pharmacophore features of DFG-in, C-helix-out compounds are analyzed in relation to DFG-out inhibitors.

BT - Bioorganic & Medicinal Chemistry Letters C1 - 0184 DA - 2014 Mar 15 DO - 10.1016/j.bmcl.2014.01.083 IS - 6 J2 - Bioorg. Med. Chem. Lett. LA - eng M3 - Research Article N2 -

The non-receptor tyrosine kinase Syk (spleen tyrosine kinase) is a pharmaceutical relevant target because its over-activation is observed in several autoimmune diseases, allergy, and asthma. Here we report the identification of two novel inhibitors of Syk by high-throughput docking into a rare C-helix-out conformation published recently. Interestingly, both compounds are slightly more active on ZAP70 (Zeta-chain-associated protein kinase 70), which is the kinase closest to Syk in the phylogenetic tree of human kinases. Taken together, the docking pose and experimental results suggest that the higher affinity of the inhibitors for ZAP70 than Syk originates from a more populated C-helix-out conformation in ZAP70. The latter observation is congruent with the 100-fold lower intrinsic activity of ZAP70 than Syk, as the C-helix-out conformation is inactive. The pharmacophore features of DFG-in, C-helix-out compounds are analyzed in relation to DFG-out inhibitors.

PY - 2014 SP - 1523 EP - 1527 T2 - Bioorganic & Medicinal Chemistry Letters TI - Discovery of dual ZAP70 and Syk kinases inhibitors by docking into a rare C-helix-out conformation of Syk VL - 24 SN - 1464-3405 ER -