1. Discovery of Lanraplenib (GS-9876): A Once-Daily Spleen Tyrosine Kinase Inhibitor for Autoimmune Diseases
- Author
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Eric B. Lansdon, Helen Yu, Kropf Jeffrey E, Peter A. Blomgren, Jennifer R. Lo, Guoju Geng, Kevin S. Currie, Aaron C. Schmitt, Jayaraman Chandrasekhar, Chris Pohlmeyer, Scott A. Mitchell, Seung H. Lee, Wanchi Fung, Sarah Wise, Jin-Ming Xiong, Zhongdong Zhao, Randall Mark Jones, Kimberly Suekawa-Pirrone, Julie Di Paolo, Bernard P. Murray, Carmen Ip, and Jianjun Xu
- Subjects
Cell type ,Systemic lupus erythematosus ,010405 organic chemistry ,business.industry ,Organic Chemistry ,Regulator ,Syk ,Drug interaction ,medicine.disease ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Immune system ,Pharmacokinetics ,Drug Discovery ,medicine ,Cancer research ,Once daily ,business - Abstract
[Image: see text] 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.
- Published
- 2019