TAK-659 是一种高效选择性、可逆的，口服有效的 SYK/FLT3 双抑制剂，对 SYK 和 FLT3 作用的 IC50 值分别为 3.2 nM、4.6 nM。TAK-659 能诱导肿瘤细胞死亡而不作用于非肿瘤细胞，具有治疗慢性淋巴细胞白血病 (CLL) 的潜力。
CAS：1312691-33-0
分子式：C17H21FN6O
分子量：344.39
纯度：98%
存储：Store at -20°C

Background:

TAK-659 is a highly potent, selective, reversible and orally available dual inhibitor of spleen tyrosine kinase (SYK) and fms related tyrosine kinase 3 (FLT3), with an IC50 of 3.2 nM and 4.6 nM for SYK and FLT3, respectively. TAK-659 induces cell death in tumor cells but not in nontumor cells, and with potential for the treatment of chronic lymphocytic leukemia (CLL)[1][2][3][4]. IC50: 3.2 nM (Syk), 4.6 nM (FLT3)[1]

TAK-659 inhibits cellular proliferation in SYK-dependent DLBCL and FLT3-dependent AML cell lines[1][3].TAK-659 (5 µM; 1-24 hours) induces Casp3 activation in the LMP2A/MYC cells which was readily apparent at 4 h and reached maximum levels at 8 h of treatment[4].TAK-659 (0.01-10 μM; 1 hour) stimulates expression of phospho-Syk at Tyr525 and Tyr352 and phospho-ERK1/2 increased in Ramos cells[2]. Apoptosis Analysis[4] Cell Line: LMP2A/MYC cells

TAK-659 (100 mg/kg/day; p.o.; for 10 days) treatment totally abrogates splenomegaly and tumor development in LMP2A/MYC mice in both pretumor and tumor cell transfer experiments[4]. TAK-659 treatment kills tumor cells, but not host cells within the spleen and tumors[4].TAK-659 treatment abrogates metastasis of tumor cells into bone marrow[4]. Animal Model: LMP2A/MYC double transgenic mice[4]

[1]. Lam B, 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. [2]. Purroy N, 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. [3]. Jie Yu, et al. Anti-tumor activity of TAK-659, a dual inhibitor of SYK and FLT-3 kinases, in AML models. Journal of Clinical Oncology 34, no. 15_suppl. [4]. Cen O, et al. Spleen Tyrosine Kinase Inhibitor TAK-659 Prevents Splenomegaly and Tumor Development in a Murine Model of Epstein-Barr Virus-Associated Lymphoma. mSphere. 2018 Aug 22;3(4).