N-Acetyl-3-aminopyrazoles block the non-canonical NF-kB cascade by selectively inhibiting NIKElectronic supplementary information (ESI) available: Additional biochemical data, chemistry, NMR characterization of final compounds, and biochemical protocols. See DOI: 10.1039/c8md00068a

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 hit-to-lead optimization process that identified the aminopyrazole 3a as a low μM selective NIK inhibitor. Compound 3a effectively inhibited the NIK-dependent activation of the NF-κB pathway in tumour cells, confirming its selective inhibitory profile. Resulting from hit-to-lead optimization, the aminopyrazole 3a is a NIK inhibitor selective over 44 kinases.