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

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2020 Apr 16

PMID 32292557

Citations 17

Authors

Peter Blomgren

Jayaraman Chandrasekhar

Julie A Di Paolo

Wanchi Fung

Guoju Geng

Carmen Ip

Randall Jones

Jeffrey E Kropf

Eric B Lansdon

Seung Lee

Jennifer R Lo

Scott A Mitchell

Bernard Murray

Chris Pohlmeyer

Aaron Schmitt

Kimberly Suekawa-Pirrone

Sarah Wise

Jin-Ming Xiong

Jianjun Xu

Helen Yu

Zhongdong Zhao

Kevin S Currie

Affiliations

Soon will be listed here.

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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