K145 hydrochloride is a selective sphingosine kinase 2 (SphK2) inhibitor with an IC50 value of 4.3μM and a Ki value of 6.4μM, exhibiting anticancer activity[1, 2]. K145 hydrochloride inhibits SphK2 activity by competitively binding to it, without affecting the homologous enzyme SphK1[3]. K145 hydrochloride can inhibit the growth of solitary plasmacytoma (SP) cells[4].
In vitro, pretreatment of breast cancer cells (MCF-7, MDA-MB-231, and LM2-4 cells) with K145 hydrochloride (2μM) significantly inhibited epidermal growth factor (EGF)-mediated cell migration and significantly reduced sphingosine-1-phosphate (S1P) levels in LM2-4 cells[5].
In vivo, K145 hydrochloride (5, 10mg/kg) administered via intraperitoneal injection for 10 days in ob/ob and db/db mice reduced hepatic lipid accumulation and lowered fasting blood glucose levels in db/db mice, and regulated the mRNA levels of lipid metabolism-related genes in the liver of ob/ob mice[6]. K145 hydrochloride (50mg/kg/day) administered via intraperitoneal injection for 30 days in glioblastoma (GBM) cell xenograft mice slowed tumor growth and increased mouse survival rate[7].
References:
[1] Liu K, Guo T L, Hait N C, et al. Biological characterization of 3-(2-amino-ethyl)-5-[3-(4-butoxyl-phenyl)-propylidene]-thiazolidine-2, 4-dione (K145 hydrochloride) as a selective sphingosine kinase-2 inhibitor and anticancer agent[J]. PloS one, 2013, 8(2): e56471.
[2] Lewis A C, Wallington-Beddoe C T, Powell J A, et al. Targeting sphingolipid metabolism as an approach for combination therapies in haematological malignancies[J]. Cell Death Discovery, 2018, 4(1): 72.
[3] Worrell B L, Brown A M, Santos W L, et al. In silico characterization of structural distinctions between isoforms of human and mouse sphingosine kinases for accelerating drug discovery[J]. Journal of chemical information and modeling, 2019, 59(5): 2339-2351.
[4] Li J, Li X J, Zhao D, et al. K145 hydrochloride, a sphingosine kinase 2 inhibitor, inhibits solitary plasmacytoma cell growth[J]. The FASEB Journal, 2018, 32: 836.14-836.14.
[5] Maiti A, Takabe K, Hait N C. Metastatic triple-negative breast cancer is dependent on SphKs/S1P signaling for growth and survival[J]. Cellular signalling, 2017, 32: 85-92.
[6] Shi Y, Wei Q, Liu Y, et al. The alleviating effect of sphingosine kinases 2 inhibitor K145 hydrochloride on nonalcoholic fatty liver[J]. Biochemical and biophysical research communications, 2021, 580: 1-6.
[7] Fei X, Dou Y, Sun K, et al. TRIM22 promotes the proliferation of glioblastoma cells by activating MAPK signaling and accelerating the degradation of Raf-1[J]. Experimental & molecular medicine, 2023, 55(6): 1203-1217.
K145 hydrochloride是一种选择性鞘磷酸酶2（SphK2）抑制剂，IC50值为4.3μM，Ki值为6.4µM，具有抗癌活性[1, 2]。K145 hydrochloride通过竞争性结合SphK2抑制其活性，对同源酶SphK1无影响[3]。K145 hydrochloride能够抑制单体浆细胞瘤（SP）细胞的生长[4]。
在体外，K145 hydrochloride（2µM）预处理乳腺癌细胞（MCF-7、MDA-MB-231、LM2-4细胞），均显著抑制了表皮生长因子（EGF）介导的细胞迁移，显著降低了LM2-4细胞内鞘氨醇-1-磷酸（S1P）水平[5]。
在体内，K145 hydrochloride（5, 10mg/kg）通过腹腔注射治疗ob/ob小鼠和db/db小鼠10天，减轻了db/db小鼠的肝脏脂质蓄积并降低了其空腹血糖水平，调节了ob/ob小鼠肝脏中脂质代谢相关基因的mRNA水平[6]。K145 hydrochloride（50mg/kg/day）通过腹腔注射治疗胶质母细胞瘤（GBM）细胞异种移植小鼠30天，减缓了肿瘤生长速度，提高了小鼠生存率[7]。