PMID- 32292557
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210409
IS  - 1948-5875 (Print)
IS  - 1948-5875 (Electronic)
IS  - 1948-5875 (Linking)
VI  - 11
IP  - 4
DP  - 2020 Apr 9
TI  - Discovery of Lanraplenib (GS-9876): A Once-Daily Spleen Tyrosine Kinase Inhibitor 
      for Autoimmune Diseases.
PG  - 506-513
LID - 10.1021/acsmedchemlett.9b00621 [doi]
AB  - 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.
CI  - Copyright (c) 2020 American Chemical Society.
FAU - Blomgren, Peter
AU  - Blomgren P
AD  - Gilead Sciences, 199 E. Blaine Street, Seattle, Washington 98102, United States.
FAU - Chandrasekhar, Jayaraman
AU  - Chandrasekhar J
AD  - Gilead Sciences, 199 E. Blaine Street, Seattle, Washington 98102, United States.
FAU - Di Paolo, Julie A
AU  - Di Paolo JA
AD  - Gilead Sciences, 333 Lakeside Drive, Foster City, California 94404, United 
      States.
FAU - Fung, Wanchi
AU  - Fung W
AD  - Gilead Sciences, 333 Lakeside Drive, Foster City, California 94404, United 
      States.
FAU - Geng, Guoju
AU  - Geng G
AD  - Gilead Sciences, 333 Lakeside Drive, Foster City, California 94404, United 
      States.
FAU - Ip, Carmen
AU  - Ip C
AD  - Gilead Sciences, 333 Lakeside Drive, Foster City, California 94404, United 
      States.
FAU - Jones, Randall
AU  - Jones R
AD  - Gilead Sciences, 199 E. Blaine Street, Seattle, Washington 98102, United States.
FAU - Kropf, Jeffrey E
AU  - Kropf JE
AD  - Gilead Sciences, 199 E. Blaine Street, Seattle, Washington 98102, United States.
FAU - Lansdon, Eric B
AU  - Lansdon EB
AD  - Gilead Sciences, 333 Lakeside Drive, Foster City, California 94404, United 
      States.
FAU - Lee, Seung
AU  - Lee S
AD  - Gilead Sciences, 199 E. Blaine Street, Seattle, Washington 98102, United States.
FAU - Lo, Jennifer R
AU  - Lo JR
AD  - Gilead Sciences, 199 E. Blaine Street, Seattle, Washington 98102, United States.
FAU - Mitchell, Scott A
AU  - Mitchell SA
AD  - Gilead Sciences, 199 E. Blaine Street, Seattle, Washington 98102, United States.
FAU - Murray, Bernard
AU  - Murray B
AD  - Gilead Sciences, 333 Lakeside Drive, Foster City, California 94404, United 
      States.
FAU - Pohlmeyer, Chris
AU  - Pohlmeyer C
AD  - Gilead Sciences, 333 Lakeside Drive, Foster City, California 94404, United 
      States.
FAU - Schmitt, Aaron
AU  - Schmitt A
AD  - Gilead Sciences, 199 E. Blaine Street, Seattle, Washington 98102, United States.
FAU - Suekawa-Pirrone, Kimberly
AU  - Suekawa-Pirrone K
AD  - Gilead Sciences, 333 Lakeside Drive, Foster City, California 94404, United 
      States.
FAU - Wise, Sarah
AU  - Wise S
AD  - Gilead Sciences, 333 Lakeside Drive, Foster City, California 94404, United 
      States.
FAU - Xiong, Jin-Ming
AU  - Xiong JM
AD  - Gilead Sciences, 199 E. Blaine Street, Seattle, Washington 98102, United States.
FAU - Xu, Jianjun
AU  - Xu J
AD  - Gilead Sciences, 199 E. Blaine Street, Seattle, Washington 98102, United States.
FAU - Yu, Helen
AU  - Yu H
AD  - Gilead Sciences, 333 Lakeside Drive, Foster City, California 94404, United 
      States.
FAU - Zhao, Zhongdong
AU  - Zhao Z
AD  - Gilead Sciences, 199 E. Blaine Street, Seattle, Washington 98102, United States.
FAU - Currie, Kevin S
AU  - Currie KS
AD  - Gilead Sciences, 199 E. Blaine Street, Seattle, Washington 98102, United States.
AD  - Gilead Sciences, 333 Lakeside Drive, Foster City, California 94404, United 
      States.
LA  - eng
PT  - Journal Article
DEP - 20200212
PL  - United States
TA  - ACS Med Chem Lett
JT  - ACS medicinal chemistry letters
JID - 101521073
PMC - PMC7153012
COIS- The authors declare no competing financial interest.
EDAT- 2020/04/16 06:00
MHDA- 2020/04/16 06:01
PMCR- 2021/04/09
CRDT- 2020/04/16 06:00
PHST- 2019/12/18 00:00 [received]
PHST- 2020/02/12 00:00 [accepted]
PHST- 2020/04/16 06:00 [entrez]
PHST- 2020/04/16 06:00 [pubmed]
PHST- 2020/04/16 06:01 [medline]
PHST- 2021/04/09 00:00 [pmc-release]
AID - 10.1021/acsmedchemlett.9b00621 [doi]
PST - epublish
SO  - ACS Med Chem Lett. 2020 Feb 12;11(4):506-513. doi: 
      10.1021/acsmedchemlett.9b00621. eCollection 2020 Apr 9.