Discovery of Lanraplenib (GS-9876): A Once-Daily Spleen Tyrosine Kinase Inhibitor for Autoimmune Diseases
Peter Blomgren, Jayaraman Chandrasekhar, Julie A. Di Paolo, Wanchi Fung, Guoju Geng, Carmen Ip, Randall M. Jones, Jeffrey E. Kropf, E.B. Lansdon, Seung Woong Lee, Jennifer R. Lo, Scott A. Mitchell, Bernard P. Murray, Chris Pohlmeyer, Aaron C. Schmitt, Kimberly Suekawa-Pirrone, Sarah Wise, Jin-Ming Xiong, Jianjun Xu, Helen Yu, Zhongdong Zhao, Kevin Currie
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.