Discovery of novel Kir4.1 inhibitors based on serdemetan with potential therapy for glioblastoma-depression comorbidity.

Primary gliomas frequently accompany depression, worsening symptoms and prognosis. Current combination therapies show limited efficacy due to poor compliance, overlapping adverse effects, and delayed antidepressant onset. To address this challenge, we aimed to develop a bifunctional agent with both antiglioma and antidepressant properties. Targeting astrocytic Kir4.1 (Kir4.1 potassium channel) in the lateral habenula has been proposed as a potential therapeutic strategy for depression, with the advantage of rapid-onset effects. Through high-throughput screening, Serdemetan (Serd), a broad-spectrum antitumor agent currently in phase I clinical trials with potent antiglioma activity, was found to exhibit moderate Kir4.1 inhibitory activity. Based on this, Serd was selected as the bifunctional lead compound. A series of structural modifications were carried out to enhance its inhibitory activity against Kir4.1 while retaining its antiglioma efficacy, resulting in 21 novel derivatives. Among these, compound 19 demonstrated improved Kir4.1 inhibition activity while maintaining potent antiglioma activity. In addition, compound 19 exhibited potential blood-brain barrier permeability. Furthermore, compared with Serd, compound 19 showed improved inhibitory selectivity for Kir4.1. Finally, the relevant electrophysiological experiments demonstrate that compound 19 could modulate native Kir4.1 channels in astrocytes. These findings support its further development for bifunctional compound to treat both glioma and depression.