The azatryptophan-based fluorescent platform for in vitro rapid screening of inhibitors disrupting IKK£]-NEMO interaction
Journal
Bioorganic Chemistry
Journal Volume
81
Pages
504-511
Date Issued
2018
Author(s)
Chao, W.-C.
Chiang, T.-H.
Chaudhari, P.D.
Lin, L.-J.
Lu, J.-F.
Hong, B.-C.
Wang, J.-S.
Lin, T.-C.
Shen, J.-Y.
Abstract
The nuclear factor-κB (NF-κB) plays an important role in inflammatory and immune responses. Aberrant NF-κB signaling is implicated in multiple disorders, including cancer. Targeting the regulatory scaffold subunit IκB kinase γ (IKKγ/NEMO) as therapeutic interventions could be promising due to its specific involvement in canonical NF-κB activation without interfering with non-canonical signaling. In this study, the use of unnatural amino acid substituted IKKβ with unique photophysical activity to sense water environment changes upon interaction with NEMO provides a powerful in vitro screening platform that would greatly facilitate the identification of compounds having the potential to disrupt IKKβ-NEMO interaction, and thus specifically modulate the canonical NF-κB pathway. We then utilized a competitive binding platform to screen the binding ability of a number of potential molecules being synthesized. Our results suggest that a lead compound (?)-PDC-099 is a potent agent with ascertained potency to disrupt IKKβ-NEMO complex for modulating NF-κB canonical pathway. ? 2018 Elsevier Inc.
Other Subjects
heterocyclic compound; I kappa B kinase beta; I kappa B kinase gamma; tryptophan derivative; water; fluorescent dye; heterocyclic compound; I kappa B kinase; IKBKG protein, human; peptide; tryptophan; aqueous solution; Article; binding site; competitive binding assay; controlled study; dissociation constant; environmental change; fluorescence; human; human cell; in vitro study; isomer; molecular interaction; priority journal; steady state; surface plasmon resonance; titrimetry; analogs and derivatives; antagonists and inhibitors; chemistry; drug effect; metabolism; molecular model; preclinical study; procedures; protein analysis; Aza Compounds; Drug Evaluation, Preclinical; Fluorescent Dyes; Humans; I-kappa B Kinase; Models, Molecular; Peptides; Protein Interaction Maps; Tryptophan
Type
journal article