6VOV

Crystal structure of Syk in complex with GS-9876

Summary for 6VOV

• Entry DOI: 10.2210/pdb6vov/pdb
• Descriptor: Tyrosine-protein kinase SYK, 6-(6-aminopyrazin-2-yl)-N-{4-[4-(oxetan-3-yl)piperazin-1-yl]phenyl}imidazo[1,2-a]pyrazin-8-amine (3 entities in total)
• Functional Keywords: spleen tyrosine kinase b-cell syk, immune system
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 66256.19

Authors

Lansdon, E.B. (deposition date: 2020-01-31, release date: 2020-03-11, Last modification date: 2023-10-11)

Primary citation

Blomgren, P.,Chandrasekhar, J.,Di Paolo, J.A.,Fung, W.,Geng, G.,Ip, C.,Jones, R.,Kropf, J.E.,Lansdon, E.B.,Lee, S.,Lo, J.R.,Mitchell, S.A.,Murray, B.,Pohlmeyer, C.,Schmitt, A.,Suekawa-Pirrone, K.,Wise, S.,Xiong, J.M.,Xu, J.,Yu, H.,Zhao, Z.,Currie, K.S.
Discovery of Lanraplenib (GS-9876): A Once-Daily Spleen Tyrosine Kinase Inhibitor for Autoimmune Diseases.
Acs Med.Chem.Lett., 11:506-513, 2020

PubMed 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.

PubMed: 32292557
DOI: 10.1021/acsmedchemlett.9b00621

Experimental method

X-RAY DIFFRACTION (1.95 Å)