Rational design of highly selective spleen tyrosine kinase inhibitors.

Abstract

A novel approach to design selective spleen tyrosine kinase (Syk) inhibitors is described. Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism for the treatment of autoimmune diseases such as asthma, rheumatoid arthritis, and SLE. Fostamatinib, a Syk inhibitor that successfully completed phase II clinical trials, also exhibits some undesirable side effects. More selective Syk inhibitors could offer safer, alternative treatments. Through a systematic evaluation of the kinome, we identified Pro455 and Asn457 in the Syk ATP binding site as a rare combination among sequence aligned kinases and hypothesized that optimizing the interaction between them and a Syk inhibitor molecule would impart high selectivity for Syk over other kinases. We report the structure-guided identification of three series of selective spleen tyrosine kinase inhibitors that support our hypothesis and offer useful guidance to other researchers in the field.

• Authors: Matthew C Lucas, David M Goldstein, Johannes C Hermann, Andreas Kuglstatter, Wenjian Liu, Kin Chun Luk, Fernando Padilla, Michelle Slade, Armando G Villaseñor, Jutta Wanner, Wenwei Xie, Xiaohu Zhang, Cheng Liao
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 23 Pg. 10414-23 (Dec 13 2012) ISSN: 1520-4804 [Electronic] United States
• PMID: 23151054 (Publication Type: Journal Article)

Chemical References

• Protein Kinase Inhibitors
• Protein-Tyrosine Kinases

Topics

• Drug Design
• Humans
• Models, Molecular
• Protein Kinase Inhibitors (chemistry, pharmacology)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Spleen (enzymology)