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

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.

Figure 1

Clinical stage SYK inhibitors.

Figure 2

Calculated electrostatic potentials (atomic unit of charge/Å) at C-ring sites due to SYK protein residues (A). Hydrogen bond donor moments derived from density functional calculations (B). Stronger donors tend to have more negative values.

Figure 3

Co-crystal structure (1.95 Å) of SYK kinase domain with 39 (PDB code 6VOV). Dashed lines show hydrogen bond contacts in the pocket between compound and protein. Part of the protein is removed to make viewing the compound binding mode easier.

Figure 4

Efficacy of 39 in the NZB/W F1 murine lupus model. 39 reduced the proteinuria score from weeks 28–40 (A) and increased overall survival at week 40 (B).