Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Molecules. 2024 May 22;29(11):2437. doi: 10.3390/molecules29112437.
Gain-of-function mutations in the gene, which encodes the sodium-activated potassium channel known as SLACK, are associated with the rare but devastating developmental and epileptic encephalopathy known as epilepsy of infancy with migrating focal seizures (EIMFS). The design of small molecule inhibitors of SLACK channels represents a potential therapeutic approach to the treatment of EIMFS, other childhood epilepsies, and developmental disorders. Herein, we describe a hit optimization effort centered on a xanthine SLACK inhibitor () discovered via a high-throughput screen. Across three distinct regions of the chemotype, we synthesized 58 new analogs and tested each one in a whole-cell automated patch-clamp assay to develop structure-activity relationships for inhibition of SLACK channels. We further evaluated selected analogs for their selectivity versus a variety of other ion channels and for their activity versus clinically relevant SLACK mutants. Selectivity within the series was quite good, including versus hERG. Analog (VU0948578) was a potent inhibitor of WT, A934T, and G288S SLACK, with IC values between 0.59 and 0.71 µM across these variants. VU0948578 represents a useful in vitro tool compound from a chemotype that is distinct from previously reported small molecule inhibitors of SLACK channels.
基因中的功能获得性突变,该基因编码称为 SLACK 的钠激活钾通道,与罕见但破坏性的发育性和癫痫性脑病有关,称为婴儿期癫痫伴移行性局灶性发作(EIMFS)。SLACK 通道的小分子抑制剂的设计代表了治疗 EIMFS、其他儿童癫痫和发育障碍的潜在治疗方法。本文描述了一项以黄嘌呤 SLACK 抑制剂 ()为中心的优化工作,该抑制剂是通过高通量筛选发现的。在该化学型的三个不同区域,我们合成了 58 种新的类似物,并在全细胞自动膜片钳测定中对每种类似物进行了测试,以开发抑制 SLACK 通道的构效关系。我们还评估了选定的类似物对各种其他离子通道的选择性以及对临床相关 SLACK 突变体的活性。该系列中的选择性相当好,包括对 hERG 的选择性。类似物 (VU0948578) 是 WT、A934T 和 G288S SLACK 的有效抑制剂,在这些变体中 IC 值在 0.59 至 0.71µM 之间。VU0948578 是一种来自与先前报道的 SLACK 通道小分子抑制剂不同的化学型的有用的体外工具化合物。