Discovery of Lanraplenib (GS-9876): A Once-Daily Spleen Tyrosine Kinase Inhibitor for Autoimmune Diseases

  • ACS Med Chem Lett. 2020 Feb 12;11(4):506-513. doi: 10.1021/acsmedchemlett.9b00621.
Peter Blomgren  1 ,  Jayaraman Chandrasekhar  1 ,  Julie A Di Paolo  2 ,  Wanchi Fung  2 ,  Guoju Geng  2 ,  Carmen Ip  2 ,  Randall Jones  1 ,  Jeffrey E Kropf  1 ,  Eric B Lansdon  2 ,  Seung Lee  1 ,  Jennifer R Lo  1 ,  Scott A Mitchell  1 ,  Bernard Murray  2 ,  Chris Pohlmeyer  2 ,  Aaron Schmitt  1 ,  Kimberly Suekawa-Pirrone  2 ,  Sarah Wise  2 ,  Jin-Ming Xiong  1 ,  Jianjun Xu  1 ,  Helen Yu  2 ,  Zhongdong Zhao  1 ,  Kevin S Currie  1  2
Affiliations
  • 1. Gilead Sciences, 199 E. Blaine Street, Seattle, Washington 98102, United States.
  • 2. Gilead Sciences, 333 Lakeside Drive, Foster City, California 94404, United States.
PMID: 32292557 DOI: 10.1021/acsmedchemlett.9b00621
Abstract

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.