N-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 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.

Fig. 1. Examples of selective NIK inhibitors A and B. PS-1145 structure of a potent IKKβ inhibitor.

Fig. 2. A schematic description of the compounds investigated in the hit-to-lead process applied to 2a.

Scheme 1. General synthesis scheme of the lead compounds with general structure formulae 2, 3 and 4. Reaction conditions: i) dry THF, NaH, reflux, overnight; ii) NH₂NH₂·2HCl, 3 Å sieves, dry EtOH, reflux, overnight; iii) R₃COCl, dry pyridine, dry THF, rt, or appropriate anhydride, dry THF, rt, from 2 h to overnight.

Fig. 3. ¹H-NMR spectra of the starting material 2a and acylated 3a–4a.

Fig. 4. Chemical shift of compounds described by Kusakiewicz-Dawid et al.

Scheme 2. Synthesis of compounds 6a and 6b. Reaction conditions: i) pyridine-2-carbonyl chloride or trifluoroacetic anhydride, dry pyridine, dry THF, rt, overnight.

Scheme 3. Methylation of 2a to give compounds 5a and 5b. Reaction conditions: i) Cs₂CO₃, CH₃I, dry THF, rt, overnight.