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Bioorg Med Chem Lett. 2014 Mar 15;24(6):1523-7. doi: 10.1016/j.bmcl.2014.01.083. Epub 2014 Feb 10.

Discovery of dual ZAP70 and Syk kinases inhibitors by docking into a rare C-helix-out conformation of Syk.

Author information

1
Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
2
Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. Electronic address: caflisch@bioc.uzh.ch.

Abstract

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.

KEYWORDS:

C-helix-out; High-throughput docking; Scoring with solvation; Syk kinase; ZAP70 kinase

PMID:
24569110
DOI:
10.1016/j.bmcl.2014.01.083
[Indexed for MEDLINE]

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