生物活性

• 靶点	Syk IC50:7.7nM

• 描述Spleen tyrosine kinase (Syk) is an intracellular cytoplasmic tyrosine kinase that mediates immunoreceptor signaling primarily in hematopoietic cells. GS-9973 is a potent, selective, and orally bioavailable Sky inhibitor with an EC₅₀ value of 26 nM^[1]. The level of phosphorylated Akt and ribosomal S6 in primary chronic lymphocytic leukemia (CLL) cells was decreased by 100 nM GS-9973 compared to control cells, while idelalisib and GS-9973 in combination (100 nM each) showed more potent inhibitory effect on Akt and ribosomal S6 phosphorylation. Compared to single agent treatment, the combination of GS-9973 (0.01 - 10 μM) and idelalisib (0.01 - 10 μM) synergistically decreased the cell viability of CLL cells isolated from the peripheral blood or bone marrow^[2]. In a rat collagen-induced arthritis model, twice daily oral dosing with GS-9973 at 10, 3, and 1 mg/kg significantly inhibited ankle inflammation. Histological analyses showed that GS-9973 inhibited cartilage damage, bone resorption, pannus formation, and peritosteal bone formation with ED₅₀ values ranging from 1.2 to 3.9 mg/kg^[1].
• 作用机制GS-9973 is a selective, orally efficacious, imidazopyrazine-based inhibitor of Syk that forms a hydrogen bond with the D512 side chain of Syk kinase^[1].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  C57BL/6 mouse bone marrow cells	-	Cytotoxic assay	4 days	Cytotoxicity against C57BL/6 mouse bone marrow cells assessed as growth inhibition preincubated for 4 days followed by [3H]-thymidine addition measured after 5 hrs by betaplate counting analysis, IC50=0.582 μM	25633741
  human MV411 cells	-	Proliferation assay	72 h	Inhibition of Flt3 in human MV411 cells assessed as assessed as proliferation after 72 hrs incubation by spectrophotometry, EC50=0.327 μM	24779514

• 动物研究
  剂量	Rat: 1 mg/kg - 10 mg/kg[1] (p.o.) Nude Mice: 20 mg/kg[3] (p.o.)
  给药途径	p.o.
  动物药代数据	Animal Rats[1] Dogs[1] Dose 0.4 mg/kg (i.v.) 1 mg/kg (p.o.) 0.4 mg/kg (i.v.) 1 mg/kg (p.o.) Administration i.v. p.o. i.v. p.o. F 67 ± 9% (p.o.) 53 ± 16% (p.o.) CL 0.27 ± 0.01 L/h/kg (i.v.) 0.80 ± 0.03 L/h/kg (i.v.) Protein binding (free drug %) 0.992 0.928 Vss 0.52 ± 0.05 L/kg (i.v.) 1.41 ± 0.40 L/kg (i.v.)

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT03013998	Previously Untreated Acute Mye... more >>loid Leukemia Collapse <<	Phase 1 Phase 2	Recruiting	December 2021	United States, Arizona ... more >> Mayo Clinic Arizona Recruiting Phoenix, Arizona, United States, 85054 Principal Investigator: Lisa Sproat, MD          United States, California UCLA Ronald Reagan Medical Center Recruiting Los Angeles, California, United States, 90095 Principal Investigator: Gary Schiller, MD          University of California, San Francisco Recruiting San Francisco, California, United States, 94143 Principal Investigator: Gabriel Mannis, MD          United States, Colorado University of Colorado Recruiting Denver, Colorado, United States, 80203 Principal Investigator: Dan Pollyea, MD          United States, Florida Mayo Clinic Florida Recruiting Jacksonville, Florida, United States, 32224 Principal Investigator: James Foran, MD          United States, Georgia Emory University Recruiting Atlanta, Georgia, United States, 30308 Principal Investigator: William Blum, MD          United States, Illinois University of Chicago Recruiting Chicago, Illinois, United States, 60637 Principal Investigator: Wendy Stock, MD          United States, Maryland University of Maryland Medical Center Recruiting Baltimore, Maryland, United States, 21201 Principal Investigator: Maria Baer, MD          United States, New York Memorial Sloan Kettering Cancer Center Recruiting New York, New York, United States, 10065 Principal Investigator: Eytan M Stein, MD          United States, Ohio Ohio State University Recruiting Columbus, Ohio, United States, 43210 Principal Investigator: John C Byrd, MD          Principal Investigator: Alice Mims, MD          Principal Investigator: Alison R Walker, MD, MPH          United States, Oregon Oregon Health & Science University Recruiting Portland, Oregon, United States, 97239 Principal Investigator: Uma Borate, MD          United States, Texas University of Texas Southwestern Recruiting Dallas, Texas, United States, 75390 Principal Investigator: Prapti Patel, MD          United States, Utah Huntsman Cancer Institute, University of Utah Recruiting Salt Lake City, Utah, United States, 84112 Principal Investigator: Michael Deininger, MD, PhD Collapse <<
  NCT02457598	B-cell Malignancies	Phase 1	Active, not recruiting	May 2022	United States, District of Col... more >>umbia Georgetown University Medical Center Washington, District of Columbia, United States, 20007 United States, Indiana Indiana University Health Goshen Center for Cancer Care Goshen, Indiana, United States, 46506 United States, Oregon Oregon Health and Science University Portland, Oregon, United States, 97239 France CHRU de Lille, Hopital Claude Huriez Lille, France, 59037 Hopital Saint Eloi Montpellier, France, 34295 Chu Haut Leveque Pessac, France, 33604 Centre Hospitalier de Lyon Sud Pierre Benite, France, 69310 Institut Universitaire du Cancer-Oncopole I.U.C.T-O Toulouse, France United Kingdom Cambridge University Hospitals NHS Foundation Trust - Addenbrooke's Hospital Cambridge, England, United Kingdom Leeds Teaching Hosptials NHS Trust, Dept of Haematology Leeds, England, United Kingdom, LS9 7TF University Hospital Southampton NHS Foundation Trust Southampton, England, United Kingdom, SO16 6YD Cardiff and Vale Health Board, Clinical Research Facility Cardiff, United Kingdom, CF14 4XW University Hospitals of Leicester NHS Trust Leicester, United Kingdom, LE1 5WW The Christie NHS Foundation Trust Manchester, United Kingdom, M20 4BX Plymouth Hospitals NHS Trust Plymouth, United Kingdom, PL6 8BG Collapse <<
  NCT03225924	DLBCL	Phase 1 Phase 2	Recruiting	September 2023	Belgium ... more >> Institut Jules Bordet Recruiting Bruxelles, Belgium, 1000 Contact: Marie MAEREVOET    +32 (0)25 55 56 85    marie.maerevoet@bordet.be    Clinique Universite Catholique de Louvain Saint-Luc Recruiting Bruxelles, Belgium, 1200 Contact: Nicole STRAETMANS    +32 (0)27 64 18 00    nicole.straetmans@uclouvain.be    University Hospital Gent Recruiting Gent, Belgium, 9000 Contact: Fritz OFFNER    +32 (0)93 32 21 32    fritz.offner@uzgent.be    Hopital Joliment Recruiting Haine-Saint-Paul, Belgium, 7100 Contact: Marie-Christine NGIRABACU    +32 (0) 64 23 50 71    mariechristine.ngirabacu@jolimont.be    Az Groeninge Recruiting Kortrijk, Belgium, 8500 Contact: Koenraad VAN EYGEN    +32 (0) 56 63 41 92    koen.vaneygen@azgroeninge.be    UCL Namur Recruiting Yvoir, Belgium Contact: Julien Depaus          France Ch de Bourg En Bresse Recruiting Bourg-en-Bresse, France, 0100 Contact: Hubert ORFEUVRE    05 31 15 63 51    horfeuvre@ch-bourg01.fr    CHU Côte de Nacre Recruiting Caen, France Contact: Christophe Fruchart          CHU Henri Mondor Recruiting Créteil, France Contact: Corinne Haioun          CHU de Dijon Recruiting Dijon, France Contact: Olivier Casasnovas          Ch de Versailles - Hopital Andre Mignot Recruiting Le Chesnay, France, 78150 Contact: Caroline BESSON    01 39 63 85 11    cbesson@ch-versailles.fr    Clinique Victor Hugo Recruiting Le Mans, France, 72000 Contact: Katell LE DU    02 43 47 94 93    k.ledu@cjb72.org    Chu de Limoges - Hopital Dupuytren Recruiting Limoges, France, 87042 Contact: Julie ABRAHAM    05 55 05 66 51    julie.abraham@chu-limoges.fr    Clinique de La Sauvegarde Recruiting Lyon, France, 69337 Contact: Isabelle MOULLET    04 37 49 18 20    i.moullet@wanadoo.fr    CHU Lyon Sud Recruiting Lyon, France Contact: Gilles Salles          CHU Montpellier Recruiting Montpellier, France Contact: Emmanuelle Tchernonog          Ch Region Mulhouse Et Sud Alsace Recruiting Mulhouse, France, 68070 Contact: Bernard DRENOU    03 89 64 77 43    drenoub@ghrmsa.fr    Hopital Necker Paris Recruiting Paris, France, 75015 Contact: David SIBON    01 44 49 52 96    david.sibon@aphp.fr    Chu de Bordeaux Recruiting Pessac, France, 33604 Contact: Kamal BOUABDALLAH    05 57 65 65 11    krimo.bouabdallah@chu-bordeaux.fr    Ch Annecy Genevois Recruiting Pringy, France, 74374 Contact: Nicolas DAGUINDEAU    04 50 63 69 50    ndaguindau@ch-annecygenevois.fr    Chu de Reims - Hopital Robert Debre Recruiting Reims, France, 51092 Contact: Eric DUROT    03 26 78 36 44    edurot@chu-reims.fr    Chu de Rennes - Pontchaillou Recruiting Rennes, France, 35033 Contact: Thierry LAMY DE LA CHAPELLE    02 99 28 42 26    thierry.lamy.de.la.chapelle@chu-rennes.fr    Ch de Roubaix-Hopital Victor Provo Recruiting Roubaix, France, 59056 Contact: Isabelle PLANTIER       isabelle.plantier@ch-roubaix.fr    Iuct Oncopole de Toulouse Recruiting Toulouse, France, 31059 Contact: Lucie OBERIC    05 31 15 63 51    oberic.lucie@iuct-oncopole.fr    Hôpital Bretonneau- Centre H. Kaplan Recruiting Tours, France, 37044 Contact: Emmanuel GYAN    02 47 47 37 12    e.gyan@chu-tours.fr    Ch de Valenciennes Recruiting Valenciennes, France, 59322 Contact: Sabine TRICOT    04 50 63 69 50    tricot-s@ch-valenciennes.fr    Chru de Nancy Recruiting Vandœuvre-lès-Nancy, France, 54511 Contact: Laurianne CLEMENT-FILLIATRE    03 83 15 32 82    la.clement@chru-nancy.fr Collapse <<

• 更多
• 参考文献

• [1] Currie KS, Kropf JE, et al. Discovery of GS-9973, a selective and orally efficacious inhibitor of spleen tyrosine kinase. J Med Chem. 2014;57(9):3856-73.

  [2] Burke RT, Meadows S, et al. A potential therapeutic strategy for chronic lymphocytic leukemia by combining Idelalisib and GS-9973, a novel spleen tyrosine kinase (Syk) inhibitor. Oncotarget. 2014;5(4):908-15.

  [3] Sun H, Lin DC, et al. Identification of a Novel SYK/c-MYC/MALAT1 Signaling Pathway and Its Potential Therapeutic Value in Ewing Sarcoma. Clin Cancer Res. 2017 Aug 1;23(15):4376-4387.