Blood–brain barrier permeability and transport studies of JLK1486: a new antiglioblastoma drug

Abstract

The knowledge of the brain permeation properties of drugs acting at the brain level is particularly important in the early phase of development and before clinical development. JLK1486 is a new anticancer drug recently reported, which in vitro evaluation on glioma cell lines is particularly promising. We reported here the HPLC analysis of cerebrospinal fluid (CSF) samples of rat injected by JLK1486. Only 0.23% of the total JLK1486 injected was found in CSF, indicating that only small amount of the drug cross the BBB, while theoretical calculations predict for this drug a high capacity of permeation. A possible hypothesis is the rapid metabolism of JLK1486 into conjugate metabolites. Relative to the possible interaction between JLK1486 and P-glycoprotein (P-gp), an ATPase assay was performed allowing to conclude that JLK1486 drug is not a good substrate for P-gp ATPase. In vivo experiments on transgenic mice brain xenografted by glioblastoma cells actually underway are required in order to confirm the in vivo antiproliferative properties of JLK1486 on glioblastoma.

JLK1486, a N,N‐[(8‐hydroxyquinoline)methyl]‐substituted benzylamine analogue, inhibits melanoma proliferation and induces autophagy

“…Using diversity‐oriented synthesis, a series of 8‐hydroxyquinoline substituted amines has previously been synthesized and reported to possess potent anti‐tumour activity; however molecular mechanisms of their action was not fully elucidated. JLK1486, a N , N ‐[(8‐hydroxyquinoline)methyl]‐substituted benzylamine, has been shown to be a potent inhibitor of glioma cell proliferation with capability of crossing the blood–brain barrier , and may thus be equally well suited to treatment of metastatic melanoma. Although anti‐proliferative activity of these compounds correlates with generation of relatively stable and moderately reactive quinone methide intermediates (which react preferentially with thiols but not with DNA amino groups), the precise molecular mechanism through which JLK1486 inhibits cell growth, also, has not been clarified.…”