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

ABSTRACT: NF-?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-?B pathway in tumour cells, confirming its selective inhibitory profile.

SUBMITTER: Pippione AC

PROVIDER: S-EPMC6071728 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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

Pippione Agnese C AC Sainas Stefano S Federico Antonella A Lupino Elisa E Piccinini Marco M Kubbutat Michael M Contreras Jean-Marie JM Morice Christophe C Barge Alessandro A Ducime Alex A Boschi Donatella D Al-Karadaghi Salam S Lolli Marco L ML

MedChemComm 20180412 6

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 ...[more]

PMID: 30108985

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