LXH254 hybrid with adamantane: synthesis and in vitro evaluation of 2,4,6-trisubstituted pyridine derivative Z-001 containing adamantyl moiety as a novel B-RAF inhibitor

In this study, 2,4,6-trisubstituted pyridine derivative Z-001 containing adamantyl moiety was designed through the hybridization strategy of LXH254 and adamantane. A new and effective synthetic route was established to achieve the synthesis of Z-001 through four step reactions, starting from commercially available 3-bromo-4-methylaniline and (2,6-dichloropyridin-4-yl) boronic acid. Besides, Z-001 was evaluated inhibitory activity against B-Raf kinase with IC₅₀ value of 37.80 nM by ADP-Glo kinase assay, and it was found that Z-001 was a more potent B-Raf Inhibitor than Vemurafinib (IC₅₀ = 78.52 nM). Furthermore, molecular docking simulations showed that Z-001 bound to DFG-out/C-helix-in conformation in the B-Raf kinase, and formed three hydrogen bonds with GLU501, ASP594 and CYS532, respectively. It was worth noting that the adamantane alcohol of Z-001 was very suitable for matching the cavities near the solvent exposed region, which was filled with adamantyl moiety and effectively utilized in the docking model. The binding mode between Z-001 and B-Raf kinase provided a reasonable explanation for Z-001 as a potential B-Raf kinase inhibitor.

Adamantyl moiety; B-RAF inhibitor; Hybridization; Z-001.