Precision targeting of inflammatory signaling nodes: a dual emphasis on therapeutic efficacy and cardiac safety

Abstract

Chronic inflammatory diseases pose a significant global health burden taking 41 millions deaths annually, necessitating innovative therapeutic strategies. Traditional drugs often exhibit limited efficacy and adverse effects, particularly cardiotoxicity associated with hERG blockade. Here, we present a novel molecule targeting the signaling protein IKKβ, crucial in mediating inflammatory responses through the NF-κB pathway. Employing a structure-based drug design approach, our developed therapeutic exhibited promising efficacy in preclinical studies. At a concentration of 10 μM, the molecule effectively modulated key inflammatory markers, including proinflammatory cytokines and the p65 transcription factor. Furthermore, it prevented IκB degradation and decreased IKKβ phosphorylation through competitive ATP inhibition. Importantly, our research emphasizes cardiac safety, a critical consideration in drug development. Patch-Clamp methods revealed no hERG protein inhibition at the same concentration, mitigating a common cause of adverse cardiac effects observed in clinical trials. Our precision medicine approach combines targeted IKKβ inhibition with rigorous safety considerations, aligning with emerging principles in personalized medicine. By strategically addressing common setbacks in chronic inflammatory disease therapeutics, our transformative research offers a comprehensive solution to alleviate the global burden of chronic inflammation while ensuring patient safety.