Open AccessDiscovery of Lanraplenib (GS-9876): A Once-Daily Spleen Tyrosine Kinase Inhibitor for Autoimmune Diseases
Author(s) -
Peter Blomgren,
Jayaraman Chandrasekhar,
Julie A. Di Paolo,
Wanchi Fung,
Guoju Geng,
Carmen Ip,
Randall M. Jones,
Jeffrey E. Kropf,
E.B. Lansdon,
Seung Lee,
Jennifer R Lo,
Scott A. Mitchell,
Bernard P. Murray,
Chris Pohlmeyer,
Aaron C. Schmitt,
K. Suekawa-Pirrone,
Sarah Wise,
Jin-Ming Xiong,
Jianjun Xu,
Helen Yu,
Zheng Zhao,
Kevin S. Currie
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00621
Subject(s) - syk , pharmacology , medicine , tyrosine kinase inhibitor , spleen , drug , tyrosine kinase , regulator , drug discovery , immunology , immune system , cancer research , chemistry , bioinformatics , biology , receptor , cancer , biochemistry , gene
Spleen tyrosine kinase (SYK) is a critical regulator of signaling in a variety of immune cell types such as B-cells, monocytes, and macrophages. Accordingly, there have been numerous efforts to identify compounds that selectively inhibit SYK as a means to treat autoimmune and inflammatory diseases. We previously disclosed GS-9973 (entospletinib) as a selective SYK inhibitor that is under clinical evaluation in hematological malignancies. However, a BID dosing regimen and drug interaction with proton pump inhibitors (PPI) prevented development of entospletinib in inflammatory diseases. Herein, we report the discovery of a second-generation SYK inhibitor, GS-9876 (lanraplenib), which has human pharmacokinetic properties suitable for once-daily administration and is devoid of any interactions with PPI. Lanraplenib is currently under clinical evaluation in multiple autoimmune indications.