title: 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.affiliation: Small Molecule Research, Discovery Chemistry, pRED, Pharma Research and Early Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, New Jersey 07110, United States. matthew.lucas@cubist.com
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Lucas
authors.forename: David M
authors.initials: DM
authors.lastname: Goldstein
authors.forename: Johannes C
authors.initials: JC
authors.lastname: Hermann
authors.forename: Andreas
authors.initials: A
authors.lastname: Kuglstatter
authors.forename: Wenjian
authors.initials: W
authors.lastname: Liu
authors.forename: Kin Chun
authors.initials: KC
authors.lastname: Luk
authors.forename: Fernando
authors.initials: F
authors.lastname: Padilla
authors.forename: Michelle
authors.initials: M
authors.lastname: Slade
authors.forename: Armando G
authors.initials: AG
authors.lastname: Villaseñor
authors.forename: Jutta
authors.initials: J
authors.lastname: Wanner
authors.forename: Wenwei
authors.initials: W
authors.lastname: Xie
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Zhang
authors.forename: Cheng
authors.initials: C
authors.lastname: Liao
mesh_terms: D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013154:Spleen / Q000201:enzymology*
chemical_list: D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases