LDK378 dihydrochloride

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

Ceritinib diHClide 是一种选择性、口服生物利用度和 ATP 竞争性 ALK 酪氨酸激酶抑制剂（IC50 为 200 pM），还抑制 IGF-1R、InsR 和 STK22D（IC50 值分别为 8、7 和 23 nM）。

Ceritinib dihydrochloride is a selective, orally bioavailable and ATP-competitive inhibitor of ALK tyrosine kinase(IC50 of 200 pM), and also inhibits IGF-1R, InsR, and STK22D (IC50 values of 8, 7, and 23 nM, respectively), shows great antitumor potencyIn vitro experiments also showed that lipopolysaccharide (LPS)-induced migration of MDSCs was similarly owing to the activation of GRK2 and upregulation of CCR2 by LPS, whereas the treatment with LDK378 partially blocked the LPS-induced phosphorylation of p38 and GRK2 and decreased the expression of CCR2 on the cell surface, therefore leading to the suppression of MDSC migration[1].?LDK378 significantly improved the survival of CLP-induced polymicrobial septic mice, which was paralleled by reduced organ injury, decreased release of inflammatory cytokines and decreased recruitment of MDSCs to the spleen.?Importantly, LDK378 inhibited the migration of MDSCs to the spleen by blocking the CLP-mediated upregulation of CC chemokine receptor 2 (CCR2), a chemokine receptor critical for the recruitment of MDSCs.?Mechanistically, LDK378 treatment blocked the CLP-induced CCR2 upregulation of MDSCs via partially inhibiting the phosphorylation of p38 and G-protein-coupled receptor kinase-2 (GRK2) in bone marrow MDSCs of septic mice.(In Vitro):Ceritinib (LDK378) shows great anti-proliferative activity in Ba/F3-NPM-ALK and Karpas290 cells with IC50 of 26.0 nM and 22.8 nM, compared with IC50 of 319.5 nM and 2477 nM in Ba/F3-Tel-InsR and Ba/F3-WT cells.(In Vivo):Ceritinib (LDK378) is designed to reduce the possibility of forming reactive metabolites and shows undetectable levels of glutathione (GSH) adducts (<1%) in liver microsomes. Ceritinib (LDK378) has relatively good metabolic stability, with moderate CYP3A4 (Midazolam substrate) inhibition and hERG inhibition. Ceritinib (LDK378) exhibits low plasma clearance in animals (mouse, rat, dog and monkey) compared to liver blood flow, with the oral bioavailability of above 55% in mouse, rat, dog and monkey. Ceritinib (LDK378) induces a dose-dependent growth inhibition and tumor regression in the Karpas299 and H2228 rat xenograft models, with no body-weight loss. Ceritinib (LDK378) shows no impact on insulin levels or plasma glucose utilization in the mouse upon chronic dosing up to 100 mg/kg.

Ceritinib (LDK378) shows great anti-proliferative activity in Ba/F3-NPM-ALK and Karpas290 cells with IC50 of 26.0 nM and 22.8 nM, compared with IC50 of 319.5 nM and 2477 nM in Ba/F3-Tel-InsR and Ba/F3-WT cells.

Ceritinib (LDK378) is designed to reduce the possibility of forming reactive metabolites and shows undetectable levels of glutathione (GSH) adducts (<1%) in liver microsomes. Ceritinib (LDK378) has relatively good metabolic stability, with moderate CYP3A4 (Midazolam substrate) inhibition and hERG inhibition. Ceritinib (LDK378) exhibits low plasma clearance in animals (mouse, rat, dog and monkey) compared to liver blood flow, with the oral bioavailability of above 55% in mouse, rat, dog and monkey. Ceritinib (LDK378) induces a dose-dependent growth inhibition and tumor regression in the Karpas299 and H2228 rat xenograft models, with no body-weight loss. Ceritinib (LDK378) shows no impact on insulin levels or plasma glucose utilization in the mouse upon chronic dosing up to 100 mg/kg.

Ceritinib dihydrochloride

Angiogenesis

ALK

ALK

Cancer

Soft Tissue Sarcoma

1380575-43-8

631.06

C28H38Cl3N5O3S

>98% (HPLC)

H2O:170 mg/mL (269.39 mM); DMSO:95 mg/mL (150.54 mM; Need ultrasonic)

Cl.Cl.CC(C)Oc1cc(C2CCNCC2)c(C)cc1Nc1ncc(Cl)c(Nc2ccccc2S(=O)(=O)C(C)C)n1

——

(-20℃)

With Ice Pack

≥ 2 years