Rational Design of Highly Selective Spleen Tyrosine Kinase Inhibitors
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- 作者：Matthew C. Lucas ; David M. Goldstein ; Johannes C. Hermann ; Andreas Kuglstatter ; Wenjian Liu ; Kin Chun Luk ; Fernando Padilla ; Michelle Slade ; Armando G. Villase帽or ; Jutta Wanner ; Wenwei Xie ; Xiaohu Zhang ; Cheng Liao
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：December 13, 2012
- 年：2012
- 卷：55
- 期：23
- 页码：10414-10423
- 全文大小：586K
- 年卷期：v.55,no.23(December 13, 2012)
- ISSN：1520-4804
文摘
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.