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

NF-kappa B-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 hit-to-lead optimization process that identified the aminopyrazole 3a as a low M selective NIK inhibitor. Compound 3a effectively inhibited the NIK-dependent activation of the NF-kappa B pathway in tumour cells, confirming its selective inhibitory profile.