Selectively targeting the IKKβ by 11,11'-methylenebisdibenzo[a, c]phenazine (SIKB-7543) downregulates aberrant NF-κB signaling to control the proliferation and induce apoptosis in Hodgkin lymphoma.

Hodgkin lymphoma (HL) develops in the part of the immune system that is centrally aggravated by the NF-κB signaling. Selectively targeting IKKβ to downregulate the NF-κB-mediated disease progression helps control this dreadful malignancy. This study evaluated novel and selective IKKβ inhibitors to downregulate aberrant NF-κB signaling in HL. GROMACS, GMX_MMPBSA, and PLIP were used after high-throughput virtual screening against the ChemBridge library to identify leads. The in vitro effectiveness was evaluated using flow cytometry, luminometry, and spectrometry on RPMI 666 and Hs 445 cells. HTVS identified SIKB-7543 with favorable binding affinities of -14.2 kcal/mol toward IKKβ. MD simulations established stable bonding for SIKB-7543 and IKKβ with RSMD values around 0.07 nm. The ΔG binding calculation was -50.46 kcal/mol, favoring sturdy binding. ADME analysis favored small-molecule characteristics. SIKB-7543 inhibited IKKβ activity with an IC₅₀ value of 118 nM. The compound effectively controlled the proliferation of RPMI 666 and Hs 445 cells with GI₅₀ values of 345.6 nM and 320.5 nM, respectively. SIKB-7543 prompted dose-responsive apoptosis in the HL cells. Cell-cycle analysis demonstrated a concentration-dependent increase in the sub-G₀ population in both cell lines following SIKB-7543 treatment, while decreasing the NF-κB-p65 (Rel A) positive populations in TNFα-stimulated RPMI 666 and Hs 445 cells dose-dependently. Results suggest SIKB-7543 is a selective IKKβ inhibitor that downregulates aberrant NF-κB signaling, controls proliferation, and induces apoptosis, warranting further preclinical developments to counter HL malignancy.