Development of Allosteric NIK Ligands from Fragment-Based NMR Screening

Jared J Anderson; Michael J Grillo; Daniel A Harki

doi:10.1021/acsmedchemlett.3c00429

Development of Allosteric NIK Ligands from Fragment-Based NMR Screening

ACS Med Chem Lett. 2023 Nov 3;14(12):1815-1820. doi: 10.1021/acsmedchemlett.3c00429. eCollection 2023 Dec 14.

Authors

Jared J Anderson¹, Michael J Grillo², Daniel A Harki^{1

2}

Affiliations

¹ Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States.
² Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States.

Abstract

NF-κB inducing kinase (NIK) is vital for the induction of many immune responses, and as such, NIK dysregulation has been implicated in various inflammatory diseases and cancers. NIK has been pursued as a potential therapeutic target, and small-molecule inhibitors that bind the orthosteric site on NIK have been reported. However, despite the established chemical matter, NIK inhibitors have not yet reached the clinic. With the goal of developing allosteric NIK ligands using a fragment-based NMR screening approach, we report the identification and development of a series of allosteric, fragment-sized NIK ligands that bind with micromolar potency and good ligand efficiency.

Abstract

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