Structure-Based Design of Tricyclic NF-κB Inducing Kinase (NIK) Inhibitors That Have High Selectivity over Phosphoinositide-3-kinase (PI3K)

Castanedo, Georgette; Blaquière, Nicole; Beresini, Maureen H.; Bravo, Brandon; Brightbill, Hans; Chen, Jacob; Cui, Haifeng; Eigenbrot, Charles; Everett, Christine; Feng, Jianwen; Godemann, Robert; Gogol, Emily; Hymowitz, S.G.; Johnson, Adam R.; Kayagaki, Nobuhiko; Kohli, Pawan Bir; Knüppel, Kathleen; Kraemer, Joachim; Krüger, Susan; Loke, Pui L.; McEwan, Paul; Montalbetti, Christian; Roberts, D. Allen; Smith, M. A.; Steinbacher, Stefan; Sujatha-Bhaskar, Swathi; Takahashi, Ryan H.; Wang, Xiaolu; Wu, Lawren C.; Zhang, Yamin; Staben, Steven T.

doi:10.1021/acs.jmedchem.6b01363

Cited by 53 publications

(55 citation statements)

References 48 publications

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“…Currently, there are 13 crystallographic structures of NIK–inhibitor complexes deposited to RCSB Protein Data Bank (PDB) 4G3D, 4IDT, 4IDV, 4G3C, 4G3E, 4G3F, 4G3G, 5T8O, 5T8P, 5T8Q, 6G4Y, and 6G4Z to afford 22 receptors file totally (see Table ).…”

Section: Resultsmentioning

confidence: 99%

“…To quantify the distinguish ability between the known inhibitors and decoys, the data set of known inhibitors and decoys were constructed. Seventy structures reported by Li et al and Castanedo et al were taken as the known inhibitors data set. Afterwards, the corresponding 3000 decoys structures were generated from the DUD‐E website based on these 70 known inhibitors.…”

Section: Resultsmentioning

confidence: 99%

“…The development of specific small‐molecule inhibitors for NIK would be a promising approach for the therapy of these diseases. So far, only a few NIK inhibitors (Figure ) have been reported in literatures, and the diversity of the scaffolds is very limited that most of the reported structures were restricted to bear a propargyl alcohol moiety. There is still an urgent need to identify new scaffolds inhibiting NIK.…”

Section: Introductionmentioning

confidence: 99%

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Identification of new NIK inhibitors by discriminatory analysis‐based molecular docking and biological evaluation

Cheng

Mei

Yan

et al. 2019

Archiv der Pharmazie

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NF-κB inducing kinase (NIK) is a key regulator in the noncanonical nuclear factor κB cells (NF-κB) signaling pathway. Dysregulation of NIK is often related with autoimmune disorders and malignancies. However, the number of reported NIK inhibitors is scarce. Discriminatory analysis-based molecular docking was used to examine the accuracy of the binding conformation and to estimate the binding affinity, leading to the identification of several new NIK inhibitors with moderate IC 50 (ranging from 48.9 to 103.4 μM). Among them, compound 5, the most potent one (IC 50 48.9 ± 6.9 μM), also showed moderate antiproliferation activity against cancer SW1990 cells, with an IC 50 value of 20.1 ± 6.0 μM. Further dynamic simulations were performed to provide more in-depth details on the binding conformation of compound 5 and the NIK protein, providing some structural clues for further optimization of compound 5 as a novel NIK inhibitor.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of new NIK inhibitors by discriminatory analysis‐based molecular docking and biological evaluation

Cheng

Mei

Yan

et al. 2019

Archiv der Pharmazie

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“…Therefore, we hypothesize that NIK and the noncanonical NF-κB are novel potential targets for developing therapeutic strategies to cure or prevent diabetes. Of note, chemical inhibitors of NIK are presently being developed (Castanedo et al 2017) and have already been successfully utilized in some animal models (Ren et al 2017). The availability of these molecules, together with development of specific mouse models, is essential to test this hypothesis.…”

Section: Resultsmentioning

confidence: 99%

The non-canonical NF-κB pathway and its contribution to β-cell failure in diabetes

Meyerovich

Ortis

Cardozo

2018

Journal of Molecular Endocrinology

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The prevalence of diabetes has reached 8.8% in worldwide population and is predicted to increase up to 10.4% by 2040. Thus, there is an urgent need for the development of means to treat or prevent this major disease. Due to its role in inflammatory responses, several studies demonstrated the importance of the transcription factor nuclear factor-κB (NF-κB) in both type 1 diabetes (T1D) and type 2 diabetes (T2D). The two major NF-κB pathways are the canonical and the non-canonical. The later pathway is activated by the NF-κB-inducing kinase (NIK) that triggers p100 processing into p52, which forms with RelB its main dimer. Cytokines mediating the activation of this pathway are present in the serum of T1D and T2D patients. Conversely, limited information is available regarding the role of the alternative pathway on diabetes development and β-cell fate. In the present review, we will briefly describe the involvement of NF-κB on diabetes pathology and discuss new studies indicating an important role for the non-canonical NF-κB activation in β-cell function and survival. The non-canonical NF-κB pathway is emerging as a novel potential target for the development of therapeutic strategies to treat or prevent diabetes.

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“…In all, this study reveals that a proteasome-resistant NIK fragment drives oncogenic NF-κB signaling in Merlin-deficient SCs. With multiple NIK small molecules currently in preclinical development (11,12), these studies provide a novel molecular insight into schwannoma genesis with highly relevant therapeutic implications.…”

Section: Introductionmentioning

confidence: 99%

A proteasome-resistant fragment of NIK mediates oncogenic NF-κB signaling in schwannomas

Gehlhausen

Hawley

Wahle

et al. 2018

Human Molecular Genetics

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Schwannomas are common, highly morbid and medically untreatable tumors that can arise in patients with germ line as well as somatic mutations in neurofibromatosis type 2 (NF2). These mutations most commonly result in the loss of function of the NF2-encoded protein, Merlin. Little is known about how Merlin functions endogenously as a tumor suppressor and how its loss leads to oncogenic transformation in Schwann cells (SCs). Here, we identify nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-inducing kinase (NIK) as a potential drug target driving NF-κB signaling and Merlin-deficient schwannoma genesis. Using a genomic approach to profile aberrant tumor signaling pathways, we describe multiple upregulated NF-κB signaling elements in human and murine schwannomas, leading us to identify a caspase-cleaved, proteasome-resistant NIK kinase domain fragment that amplifies pathogenic NF-κB signaling. Lentiviral-mediated transduction of this NIK fragment into normal SCs promotes proliferation, survival, and adhesion while inducing Significance Statement We report the discovery of a novel, proteasome-resistant fragment of NIK that drives schwannoma formation. This NIK/NF-κB signaling axis directs an autocrine HGF-c-Met signaling loop that sustains schwannoma proliferation, identifying vulnerabilities with future therapeutic potential.

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Structure-Based Design of Tricyclic NF-κB Inducing Kinase (NIK) Inhibitors That Have High Selectivity over Phosphoinositide-3-kinase (PI3K)

Cited by 53 publications

References 48 publications

Identification of new NIK inhibitors by discriminatory analysis‐based molecular docking and biological evaluation

Identification of new NIK inhibitors by discriminatory analysis‐based molecular docking and biological evaluation

The non-canonical NF-κB pathway and its contribution to β-cell failure in diabetes

A proteasome-resistant fragment of NIK mediates oncogenic NF-κB signaling in schwannomas

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