Ceritinib mesylate

Ceritinib (LDK378) mesylate is a selective and orally bioavailable ALK tyrosine kinase inhibitor that binds to ATP, with an IC50 value of 200 picomoles. Additionally, Ceritinib mesylate can inhibit IGF-1R, InsR, and STK22D, with IC50 values of 8, 7, and 23 nanomoles, respectively. It exhibits significant antitumor activity.

Ceritinib (LDK378) effectively inhibits RET (IC 50 = 400 nM), FGFR3 (IC 50 = 430 nM), LCK (IC 50 = 560 nM), JAK2 (IC 50 = 610 nM), Aurora (IC 50 = 660 nM), LYN (IC 50 = 840 nM), EGFR (IC 50 = 900 nM), and FGFR4 (IC 50 = 950 nM). It exhibits high potency against ALK kinase activity with an IC 50 value of 200 pM and selectively inhibits IGF-1R, InsR, and STK22D over a panel of 46 kinases, with a selectivity threshold of 70-fold. In Ba/F3 cells transfected with various kinases, Ceritinib inhibits ALK activity with an IC 50 of 40.7 nM, while showing IC 50 values greater than 100 nM against all other tested kinases. Ceritinib demonstrates significant antiproliferative activity in Karpas 299 human non-Hodgkin's Anaplastic Large Cell Lymphoma with the NPM-ALK fusion gene, showing IC 50 values of 22.8 nM, and in Ba/F3 cells transfected with the NPM-ALK fusion gene, where the IC 50 is 26 nM. Additionally, Ceritinib shows good selectivity in wild-type Ba/F3 cells (IC 50 > 2 μM) and in Ba/F3 cells transfected with the Tel-InsR gene (IC 50 = 320 nM).

Ceritinib (LDK378) exhibits dose-dependent inhibition of tumor growth and causes partial regression in the Karpas 299 rat xenograft model with daily dosing. It achieves complete regression in the H2228 NSCLC rat xenograft model with the EML4-ALK fusion gene. Additionally, Ceritinib (LDK378) is well tolerated in both animal models.