Amlexanox

This study evaluated whether the IKBKE inhibitor amlexanox could overcome temozolomide (TMZ) resistance in glioblastoma multiforme (GBM). In primary glioma cells and U87 MG cells, TMZ plus amlexanox synergistically induced apoptosis, reduced viability, and inhibited migration and invasion. Amlexanox reduced IKBKE expression without affecting AMPK, while the combination reversed TMZ‑induced Akt activation and suppressed mTOR phosphorylation. In a xenograft mouse model, the combination reduced tumor volume and prolonged median survival compared to either agent alone. The authors conclude that amlexanox sensitizes GBM cells to TMZ at least partly through IKBKE suppression and attenuation of TMZ‑driven Akt activation, offering a promising clinical strategy.

Fig. 1 TMZ combined with amlexanox effectively inhibited the proliferation of U87 MG and primary GBM cells. (Xiong J, et al., 2021)

Crystal structures of TBK1 in complex with amlexanox and analogs revealed that the carboxylic acid moiety and Thr156 residue are critical for potency. Removal of the acid or mutation of Thr156 reduced TBK1 inhibition, while IKKε was less affected, possibly due to greater hinge flexibility. A tetrazole bioisostere improved in vitro potency to 200 nM (IKKε) and 400 nM (TBK1), but no analog outperformed amlexanox in adipocyte assays, likely due to pharmacokinetic differences. These structural insights guide future development of amlexanox‑based inhibitors for metabolic diseases.

Fig. 2 Adipocyte cellular responses upon treatment with amlexanox (1) and selected analogs.(Beyett TS, et al., 2018)