Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase of the insulin receptor superfamily. Altered expression and hyperactivation of ALK as a consequence of translocations or point mutations has been demonstrated to be an essential oncogenic lesion in a number of cancers. LDK378 2HCl, which is currently in Phase 1 and 2 clinical trials, is a potent ALK inhibitor with an IC50 of 0.2 nM in a cell-free assay. It also inhibits IGF-1R, InSR, STK22D and FLT3 with IC50 values of 8 nM, 7 nM, 23 nM and 60 nM, respectively. LDK378 exhibited antiproliferative activity especially on BA/F3-NPM-ALK and Karpas290 cells with IC50 values of 26.0 nM and 22.8 nM, and on BA/F3-TEL-INSR and BA/F3-WT cells with IC50 values of 319.5 nM and 2477 nM, respectively. In 2-week Karpas299 rat xenograft models, LDK378 induced a dose-dependent growth inhibition (tumor growth inhibition factor [T/C] = 74% at 6.25 mg/kg; T/C = 30% at 12.5 mg/kg) and tumor regression (T/C = -33% at 25 mg/kg and T/C = -66% at 50 mg/kg). In 2-week H2228 rat xenograft models, LDK378 induced a dose-dependent growth inhibition (T/C = 67% at 5 mg/kg; T/C = 2% at 10 mg/kg) and complete tumor regression at 25mg/kg (T/C = -100% at 25 mg/kg). Moreover, LDK378 was well tolerated and no body weight loss was observed at all doses tested in both models[2].
作用机制
The central pyrimidine ring of LDK378 is sandwiched between Ala1148 and Leu1256 and its chlorine substituent is directed towards the back of the pocket making hydrophobic contact with gatekeeper Leu1196[2].
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