7SZR

NIK bound to inhibitor G02792917

Summary for 7SZR

• Entry DOI: 10.2210/pdb7szr/pdb
• Descriptor: Mitogen-activated protein kinase kinase kinase 14, SULFATE ION, 1-(3-{[(1R,4R,5S)-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl]ethynyl}phenyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (3 entities in total)
• Functional Keywords: kinase, inhibitor, nf-kb inducing kinase, signaling protein
• Biological source: Mus musculus (house mouse)
• Total number of polymer chains: 2
• Total formula weight: 78954.52

Authors

Liau, N.P.D.,Hymowitz, S.G. (deposition date: 2021-11-29, release date: 2023-06-07, Last modification date: 2023-12-20)

Primary citation

Crawford, J.J.,Feng, J.,Brightbill, H.D.,Johnson, A.R.,Wright, M.,Kolesnikov, A.,Lee, W.,Castanedo, G.M.,Do, S.,Blaquiere, N.,Staben, S.T.,Chiang, P.C.,Fan, P.W.,Baumgardner, M.,Wong, S.,Godemann, R.,Grabbe, A.,Wiegel, C.,Sujatha-Bhaskar, S.,Hymowitz, S.G.,Liau, N.,Hsu, P.L.,McEwan, P.A.,Ismaili, M.H.A.,Landry, M.L.
Filling a nick in NIK: Extending the half-life of a NIK inhibitor through structure-based drug design.
Bioorg.Med.Chem.Lett., 89:129277-129277, 2023

PubMed Abstract: Inhibition of NF-κB inducing kinase (NIK) has been pursued as a promising therapeutic target for autoimmune disorders due to its highly regulated role in key steps of the NF-κB signaling pathway. Previously reported NIK inhibitors from our group were shown to be potent, selective, and efficacious, but had higher human dose projections than desirable for immunology indications. Herein we report the clearance-driven optimization of a NIK inhibitor guided by metabolite identification studies and structure-based drug design. This led to the identification of an azabicyclo[3.1.0]hexanone motif that attenuated in vitro and in vivo clearance while maintaining NIK potency and increasing selectivity over other kinases, resulting in a greater than ten-fold reduction in predicted human dose.

PubMed: 37105490
DOI: 10.1016/j.bmcl.2023.129277

Experimental method

X-RAY DIFFRACTION (2.8 Å)