Scaffold-Hopping Approach To Discover Potent, Selective, and Efficacious Inhibitors of NF-κB Inducing Kinase

Blaquière, Nicole; Castanedo, Georgette; Burch, Jason D.; Berezhkovskiy, Leonid M.; Brightbill, Hans; Brown, Suzanne; Chan, Connie; Chiang, Po‐Chang; Crawford, James J.; Dong, Teresa; Fan, Peter W.; Feng, Jianwen; Ghilardi, Nico; Godemann, Robert; Gogol, Emily; Grabbe, Alice; Hole, A.J.; Hu, Baihua; Hymowitz, S.G.; Ismaili, Moulay Hicham Alaoui; Lê, Hòa; Lee, Patrick; Lee, Wyne; Lin, Xingyu; Liu, Ning; McEwan, Paul; McKenzie, Brent; Silvestre, H.L.; Suto, Eric; Sujatha-Bhaskar, Swathi; Wu, Guosheng; Wu, Lawren C.; Zhang, Yamin; Zhong, Zoë; Staben, Steven T.

doi:10.1021/acs.jmedchem.8b00678

Cited by 41 publications

(45 citation statements)

References 34 publications

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“…While large improvements in potency and kinase selectivity were obtained with the development of compound 2 , it was insufficiently robust for in vivo evaluation of NIK pharmacology. A recent publication by the same group [ 166 ] has reported compound 3 ( Figure 4 ), a highly potent and selective NIK inhibitor with suitable properties for advanced ADME and pharmacology experiments that will prove to be a useful tool to dissect the roles of NIK and IKKα with respect to the non-canonical NF-κB pathway in cancer.…”

Section: Targeting the Ikkα And Nik Protein Kinases With Small Molmentioning

confidence: 99%

Inhibitory-κB Kinase (IKK) α and Nuclear Factor-κB (NFκB)-Inducing Kinase (NIK) as Anti-Cancer Drug Targets

Paul

Edwards

Pepper

et al. 2018

Cells

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The cellular kinases inhibitory-κB kinase (IKK) α and Nuclear Factor-κB (NF-κB)-inducing kinase (NIK) are well recognised as key central regulators and drivers of the non-canonical NF-κB cascade and as such dictate the initiation and development of defined transcriptional responses associated with the liberation of p52-RelB and p52-p52 NF-κB dimer complexes. Whilst these kinases and downstream NF-κB complexes transduce pro-inflammatory and growth stimulating signals that contribute to major cellular processes, they also play a key role in the pathogenesis of a number of inflammatory-based conditions and diverse cancer types, which for the latter may be a result of background mutational status. IKKα and NIK, therefore, represent attractive targets for pharmacological intervention. Here, specifically in the cancer setting, we reflect on the potential pathophysiological role(s) of each of these kinases, their associated downstream signalling outcomes and the stimulatory and mutational mechanisms leading to their increased activation. We also consider the downstream coordination of transcriptional events and phenotypic outcomes illustrative of key cancer ‘Hallmarks’ that are now increasingly perceived to be due to the coordinated recruitment of both NF-κB-dependent as well as NF-κB–independent signalling. Furthermore, as these kinases regulate the transition from hormone-dependent to hormone-independent growth in defined tumour subsets, potential tumour reactivation and major cytokine and chemokine species that may have significant bearing upon tumour-stromal communication and tumour microenvironment it reiterates their potential to be drug targets. Therefore, with the emergence of small molecule kinase inhibitors targeting each of these kinases, we consider medicinal chemistry efforts to date and those evolving that may contribute to the development of viable pharmacological intervention strategies to target a variety of tumour types.

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Section: Targeting the Ikkα And Nik Protein Kinases With Small Molmentioning

confidence: 99%

Inhibitory-κB Kinase (IKK) α and Nuclear Factor-κB (NFκB)-Inducing Kinase (NIK) as Anti-Cancer Drug Targets

Paul

Edwards

Pepper

et al. 2018

Cells

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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%

“…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%

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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“…In addition, antibodies and peptides against the programmed cell death 1 (PD-1) protein and its ligand PD-L1 are also heavily investigated [ 80 ], where PD-L1 can be induced by canonical NF-κB signaling [ 81 ]. Development of IKK inhibitors persists [ 59 ], whereas development of NIK inhibitors is also ongoing [ 82 , 83 ]. Recently, a novel NIK inhibitor called Cpd33 is reported to inhibit RANKL-induced osteoclastogenesis in an ovariectomized mouse model [ 84 ].…”

Section: MM Therapy: a Steep Road To Successmentioning

confidence: 99%

“…In this regard, peptide inhibitors against L-plastin that inhibit osteoclast activity [ 102 , 115 ] might be tested. Alternatively, NIK inhibitors under development [ 82 , 83 ], or shown to repress inflammation in other mouse models [ 84 , 85 ], may be tested in MM mouse models too.…”

Section: Future Direction: Biomarker-guided Targeted Therapymentioning

confidence: 99%

Targeting NF-κB Signaling for Multiple Myeloma

Wong

Shin

Tergaonkar

et al. 2020

Cancers

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Multiple myeloma (MM) is the second most common hematologic malignancy in the world. Even though survival rates have significantly risen over the past years, MM remains incurable, and is also far from reaching the point of being managed as a chronic disease. This paper reviews the evolution of MM therapies, focusing on anti-MM drugs that target the molecular mechanisms of nuclear factor kappa B (NF-κB) signaling. We also provide our perspectives on contemporary research findings and insights for future drug development.

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Scaffold-Hopping Approach To Discover Potent, Selective, and Efficacious Inhibitors of NF-κB Inducing Kinase

Cited by 41 publications

References 34 publications

Inhibitory-κB Kinase (IKK) α and Nuclear Factor-κB (NFκB)-Inducing Kinase (NIK) as Anti-Cancer Drug Targets

Inhibitory-κB Kinase (IKK) α and Nuclear Factor-κB (NFκB)-Inducing Kinase (NIK) as Anti-Cancer Drug Targets

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

Targeting NF-κB Signaling for Multiple Myeloma

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