生物活性

• 描述Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils^[3]. TAK-659 hydrochloride is a potent, selective and orally available spleen tyrosine kinase (Syk) inhibitor with an IC₅₀ of 3.2 nM^[3]. In a cell proliferation assay, TAK-659 shows inhibition toward a SYK-dependent cell line (OCILY10)^[3]. TAK-659 inhibited the microenvironment-induced activation of Syk and downstream signaling molecules, without inhibiting the protein homologue ZAP-70 in T cells. Importantly, the pro-survival, proliferative, chemoresistant and activation effects promoted by the microenvironment were abrogated by TAK-659, which furthermore blocked CLL cell migration toward BMSC, CXCL12, and CXCL13^[4]. TAK-659 blocks anti-IgD (immune-globulin D antibody) stimulated CD86 expression in mouse peripheral B cells in vivo. In the OCI-LY10 xenograft and DLBCL PHTX-95L (primary human tumor graft from DLBCL patient) mouse models, TAK-659 demonstrates potent tumor growth inhibition (TGI) after 20 days of treatment. In the FLT3-dependent MV4-11 xenograft model, TAK-659 shows tumor regression at 60 mg/kg daily after 20 days of dosing^[3].

• 动物研究
  剂量	Mice: 60 mg/kg/day[2] (p.o.), 100 mg/kg[3] (p.o.)
  给药途径	p.o.

• 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
  NCT02954406	Lymphoma, Non-Hodgkin	Phase 1	Recruiting	April 26, 2019	United States, Arizona ... more >> University of Arizona Cancer Center, Tucson Recruiting Tucson, Arizona, United States, 85724 United States, California University of California San Diego (UCSD) - Moores Cancer Center Recruiting La Jolla, California, United States, 92093 Cedars-Sinai Medical Center (CSMC) - Samuel Oschin Comprehensive Cancer Institute Not yet recruiting West Hollywood, California, United States, 90048 United States, Kentucky University of Louisville Kentucky James Graham Brown Cancer Center Recruiting Louisville, Kentucky, United States, 40202 United States, Maryland Center for Cancer and Blood Disorders Recruiting Bethesda, Maryland, United States, 20817 United States, Massachusetts Tufts Medical Center Not yet recruiting Boston, Massachusetts, United States, 02111 United States, Michigan Henry Ford Hospital Recruiting Detroit, Michigan, United States, 48202-2608 United States, New York NYU Langone Medical Center - NYU Medical Oncology Associates Recruiting New York, New York, United States, 10016-4744 United States, North Carolina University of North Carolina - Lineberger Comprehensive Cancer Center Recruiting Chapel Hill, North Carolina, United States, 27514 United States, Ohio University Hospitals of Cleveland Recruiting Cleveland, Ohio, United States, 44106 United States, West Virginia West Virginia University Recruiting Morgantown, West Virginia, United States, 26506 Canada, Nova Scotia Queen Elizabeth II Health Sciences Centre Recruiting Halifax, Nova Scotia, Canada, B3H 2Y9 Canada, Quebec McGill University - Jewish General Hospital Recruiting Montreal, Quebec, Canada, H3T 1E2 Collapse <<
  NCT03742258	Diffuse Large B-Cell Lymphoma ... more >> Diffuse Large B-Cell Lymphoma Activated B-Cell Type Diffuse Large B-Cell Lymphoma Germinal Center B-Cell Type Diffuse Large B-Cell Lymphoma, Not Otherwise Specified High Grade B-Cell Lymphoma With MYC and BCL2 and/or BCL6 Rearrangements High Grade B-Cell Lymphoma, Not Otherwise Specified T-Cell/Histiocyte-Rich Large B-Cell Lymphoma Collapse <<	Phase 1	Not yet recruiting	August 1, 2021	United States, Illinois ... more >> Northwestern University Not yet recruiting Chicago, Illinois, United States, 60611 Contact: Reem Karmali    312-695-0711    reem.karmali@northwestern.edu    Principal Investigator: Reem Karmali Collapse <<
  NCT03742258	Diffuse Large B-Cell Lymphoma ... more >> Diffuse Large B-Cell Lymphoma Activated B-Cell Type Diffuse Large B-Cell Lymphoma Germinal Center B-Cell Type Diffuse Large B-Cell Lymphoma, Not Otherwise Specified High Grade B-Cell Lymphoma With MYC and BCL2 and/or BCL6 Rearrangements High Grade B-Cell Lymphoma, Not Otherwise Specified T-Cell/Histiocyte-Rich Large B-Cell Lymphoma Collapse <<	Phase 1	Not yet recruiting	August 1, 2021	United States, Illinois ... more >> Northwestern University Not yet recruiting Chicago, Illinois, United States, 60611 Contact: Reem Karmali    312-695-0711    reem.karmali@northwestern.edu    Principal Investigator: Reem Karmali Collapse <<

• 参考文献

• [1] Purroy N, Carabia J, et al. Inhibition of BCR signaling using the Syk inhibitor TAK-659 prevents stroma-mediated signaling in chronic lymphocytic leukemia cells. Oncotarget. 2017 Jan 3;8(1):742-756.

  [2] Lam B, Arikawa Y, et al. Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK). Bioorg Med Chem Lett. 2016 Dec 15;26(24):5947-5950.

  [3] Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z. Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK). Bioorg Med Chem Lett. 2016 Dec 15;26(24):5947-5950. doi: 10.1016/j.bmcl.2016.10.087. Epub 2016 Nov 2. PMID: 27839918.

  [4] Purroy N, Carabia J, Abrisqueta P, Egia L, Aguiló M, Carpio C, Palacio C, Crespo M, Bosch F. Inhibition of BCR signaling using the Syk inhibitor TAK-659 prevents stroma-mediated signaling in chronic lymphocytic leukemia cells. Oncotarget. 2017 Jan 3;8(1):742-756. doi: 10.18632/oncotarget.13557. PMID: 27888629; PMCID: PMC5352193.