Identification of Novel Anaplastic Lymphoma Kinase (ALK) Inhibitors Using a Common Feature Pharmacophore Model Derived from Known Ligands Crystallized with ALK

Abstract

In this investigation, a common feature pharmacophore model of anaplastic lymphoma kinase inhibitors was developed based on several known anaplastic lymphoma kinase inhibitors that were co-crystallized with anaplastic lymphoma kinase. The established pharmacophore model Hypo1 was carefully validated and then adopted to screen two in silico chemical databases, Specs (202 408 compounds) and Enamine (1 105 894 compounds), for retrieving novel anaplastic lymphoma kinase inhibitors. The hit compounds were further filtered using a fast bumping-check tool and molecular docking. Finally, 25 compounds were selected and purchased from market. The bioactivity of these compounds was firstly measured at the cellular level against a typical anaplastic lymphoma kinase mutant-driven cancer cell line, Karpas299. And six of them showed a good anti-viability activity. The kinase inhibitory potency against the recombinant human anaplastic lymphoma kinase kinase was tested to the most active compound at the cellular level, T0508-5181 (from Specs), which gave a half maximal inhibitory concentration (IC(50)) of 5.3 μM.

Latest perspectives of orally bioavailable 2,4-diarylaminopyrimidine analogues (DAAPalogues) as anaplastic lymphoma kinase inhibitors: discovery and clinical developments

“…[181][182][183] Due to inclusion of above said technologies in drug discovery campaigns, the current decade (2007-2017) has dragged prodigious progress globally in NSCLC pertaining to drug development and in clinical settings. [183][184][185][186][187] Novel targeted antineoplastic agents loaded with anticancer warhead to demonstrate imperious efficacy have been synthesized and introduced for clinical use. Second generation DAAPlouges including alectinib are known to be effective in greater than 50% NSCLC patients who were refractory to crizotinib.…”

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“…With these reports in this study, we also tried to further elucidate the requirement of the essential groups or features in the 3D space with a pharmacophore modeling tool. We have successfully implemented and reported the pharmacophore modeling using both HipHop and HypoGen modules for drug discovery and research in diabetes, cancer, tuberculosis and Alzheimer's disease 6 .…”