Structure-Based Design of Tricyclic NF-κB Inducing Kinase (NIK) Inhibitors That Have High Selectivity over Phosphoinositide-3-kinase (PI3K)

We report here structure-guided optimization of a novel series of NF-κB inducing kinase (NIK) inhibitors. Starting from a modestly potent, low molecular weight lead, activity was improved by designing a type 11/2 binding mode that accessed a back pocket past the methionine-471 gatekeeper. Divergent binding modes in NIK and PI3K were exploited to dampen PI3K inhibition while maintaining NIK inhibition within these series. Potent compounds were discovered that selectively inhibit the nuclear translocation of NF-κB2 (p52/REL-B) but not canonical NF-κB1 (REL-A/p50).本研究报道了一类新型核因子κB诱导激酶（NF-κB inducing kinase, NIK）抑制剂的结构导向优化工作。该系列以活性中等、分子量较低的先导化合物为起点，通过设计可跨越甲硫氨酸-471守门残基、进入背口袋的11/2型结合模式，提升了化合物的活性。研究团队利用NIK与PI3K间的差异化结合模式，在该系列化合物中保留了对NIK的抑制活性，同时减弱了对PI3K的抑制作用。最终获得的强效化合物可选择性抑制NF-κB2（p52/REL-B）的核转位，却不影响经典NF-κB1（REL-A/p50）通路。