2. Academic Validation
  3. Discovery of Lanraplenib (GS-9876): A Once-Daily Spleen Tyrosine Kinase Inhibitor for Autoimmune Diseases

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

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.

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