<i>N</i>-Acetyl-3-aminopyrazoles block the non-canonical NF-kB cascade by selectively inhibiting NIK

Abstract

NF-κB-inducing kinase (NIK), an oncogenic drug target that is associated with various cancers, is a central signalling component of the non-canonical pathway. A blind screening process, which established that amino pyrazole related scaffolds have an effect on IKKbeta, led to a <i>hit-to-lead</i> optimization process that identified the aminopyrazole <b>3a</b> as a low μM selective NIK inhibitor. Compound <b>3a</b> effectively inhibited the NIK-dependent activation of the NF-κB pathway in tumour cells, confirming its selective inhibitory profile.