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(IKK) Α and Nuclear Factor-Κb (Nfκb)-Inducing Kinase (NIK) As Anti-Cancer Drug Targets

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(IKK) Α and Nuclear Factor-Κb (Nfκb)-Inducing Kinase (NIK) As Anti-Cancer Drug Targets cells Review Inhibitory-κB Kinase (IKK) α and Nuclear Factor-κB (NFκB)-Inducing Kinase (NIK) as Anti-Cancer Drug Targets Andrew Paul 1,*, Joanne Edwards 2 , Christopher Pepper 3 and Simon Mackay 1 1 Strathclyde Institute of Pharmacy and Biomedical Sciences, 161 Cathedral Street, University of Strathclyde, Glasgow G4 0NR, UK; [email protected] 2 Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1QH, UK; [email protected] 3 Brighton and Sussex Medical School, University of Sussex, Brighton BN1 9PX, U.K.; [email protected] * Correspondence: [email protected]; Tel.: +44-(0)141-548-2028 Received: 20 September 2018; Accepted: 17 October 2018; Published: 20 October 2018 Abstract: 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. Keywords: inhibitory-κB kinase (IKK) α; Nuclear Factor-κB (NF-κB); NF-κB-inducing kinase (NIK); cancer; inflammation; small molecule kinase inhibitor 1. Introduction and Background 1.1. Nuclear Factor Kappa-B (NF-kB) Proteins Nuclear Factor kappa-B (NF-κB), from the Nuclear factor kappa-light-chain-enhancer of B-cells, represents a family of five transcription factors involved in diverse biological responses that underpin phenotypic outcomes of inflammation, modulation of immune responses, cell growth, proliferation, apoptosis and aspects of differentiation and development [1–5]. NF-κB signalling is now appreciated as Cells 2018, 7, 176; doi:10.3390/cells7100176 www.mdpi.com/journal/cells Cells 2018, 7, 176 2 of 30 Cells 2018, 7, 176 2 of 28 eitheras either canonical canonical (classical) (classical) or non-canonical or non-canonical (alternative) (alternative) pathways pathways via the via mobilisation the mobilisation of both of homo- both andhomo- hetero-dimer and hetero-dimer complexes complexes of these familyof these members family (seemembers Figure (see1; References Figure 1; [ 1References–5]). Collectively, [1–5]). theCollectively, NF-κB proteins the NF- areκB five proteins distinct are isoforms; five distinct RelA isoforms; (p65), RelB, RelA c-Rel, (p65), NF- RelB,κB1 c-Rel, (p105/p50) NF-κB1 and (p105/p50) NF-κB2 (p100/p52)and NF-κB2 [1 –(p100/p52)5]. In an inactive [1–5]. stateIn an these inactive proteins state are these typically proteins associated are typically with inhibitory- associatedκB (IwithκB) proteins,inhibitory- includingκB (IκB) proteins, isoforms including of IκBα,I isoformsκBβ, and of Iκ IBκ"Bαand, IκB inβ, the and case IκBε of and p105 in andthe case p100 of proteins p105 and it isp100 their proteins intrinsic it is protein their intrinsic structure protein that maintainsstructure that them maintains in a self-bound them in inhibiteda self-bound form inhibited by virtue form of theirby virtue C-terminal of their I κC-terminalB-like structures IκB-like (Iκ structuresBδ and IκB (Iγκrespectively)Bδ and IκBγ composedrespectively) of ankyrincomposed repeats of ankyrin [1–5]. Activationrepeats [1–5]. and Activation liberation and of NF- liberationκB proteins of NF- occurκB proteins typically occur in response typically to in a response number ofto extracellulara number of ligands,extracellular as well ligands, as agents as well that as agents generate that a generate DNA Damage a DNA response Damage (DDR),response resulting (DDR), resulting in the nuclear in the localisationnuclear localisation of DNA-binding of DNA-binding protein dimersprotein followingdimers following dissociation dissociation from Iκ Bfrom molecules IκB molecules [1–5]. [1–5]. Figure 1.1. SchematicSchematic representationrepresentation of of Nuclear Nuclear Factor- Factor-κBκB (NF- (NF-κB)-inducingκB)-inducing kinase kinase (NIK)-inhibitory- (NIK)-inhibitory-κB kinaseκB kinase (IKK) (IKK)α and α and IKK IKKβ-mediatedβ-mediated cell cell signalling signalling encompassing encompassing the the non-canonicalnon-canonical NF-NF-κB cascade, canonical NF-κB cascade and potential IKKα-dependent, NF-κB-independent pathways (e.g., by the dashed line). 1.2. Activation of the Non-Canonical NF-kκB Pathway The canonical pathway (reviewed elsewhere in this issue and previously in References [6,7]), [6,7]), α β can be activated in response to cytokines such as TNF α and IL-1 β andand pathogen-associated pathogen-associated molecular profilesprofiles (PAMPs)(PAMPs) suchsuch asas thethe bacterialbacterial endotoxinendotoxin lipopolysaccharidelipopolysaccharide (LPS)(LPS) [[6,7].6,7]. This response is κ α β γ typically rapidrapid and and transient, transient, mediated medi byated the by classical the classical inhibitory- inhibitory-B kinaseκ (IKK)B kinase complex (IKK) (IKK complex/ / ) β κ with(IKKα a/β requirement/γ) with a requirement for IKK -mediated for IKKβ-mediated phosphorylation phosphorylation of selected of I selectedB proteins IκB [ 6proteins,7]. In contrast, [6,7]. In κ activationcontrast, activation of the non-canonical of the non-canonical NF- B pathway NF-κB is pathway relatively is slower relatively and overslower a period and over of hours a period results of α inhours an IKK results-mediated in an IKK liberationα-mediated of predominately liberation of p52-RelB predominately dimers top52-RelB drive gene dimers transcription to drive [gene1–7]. Thistranscription slower response [1–7]. This reflects slower reliance response upon reflects protein reliance expression/stabilisation upon protein expression/stabilisation within the upstream α β componentswithin the upstream of the pathway components (see of below). the pathway Whilst (see TNF below).and Whilst IL-1 TNFhaveα theand ability IL-1β have to activate the ability the κ non-canonicalto activate the NF-non-canonicalB pathway, NF- it isκB typically pathway, alternative it is typically members alternative of the greatermembers TNF of superfamilythe greater TNF that β β drivesuperfamily activation that (see drive References activation [3,4 ]).(see This References includes lymphotoxin-[3,4]). This includes(LT- ), lymphotoxin- the related tumourβ (LT- necrosisβ), the factorrelated superfamily tumour necrosis member factor 14 superfamily (TNFSF14) member known as 14 LIGHT, (TNFSF14) TNF-like known weak as LIGHT, inducer TNF-like of apoptosis weak inducer of apoptosis (TWEAK), CD40 ligand (CD40L), Receptor-activator of NF-κB ligand (RANKL) and B-cell activating factor (BAFF), all reviewed extensively elsewhere [1,3,4]. Cells 2018, 7, 176 3 of 28 1.3. Major Components of The Receptor Activated Non-Canonical NF-κB Pathway Through a combination of molecular and genetic studies, we now appreciate receptor-mediated- non-canonical NF-κB activation to be built around the paradigm of a TNF super family ligand activating its cognate receptor via recruitment of a sequence of identifiable adaptor molecules of the TNF-Receptor associated factor (TRAF) family, notably TRAF2 and TRAF3, modulators of ubiquitination and associated protein degradation in the form of the cellular inhibitors of apoptosis (cIAPs). These proteins enable engagement and activation of the cellular kinases NF-κB-inducing kinase (NIK; see Figure 2A), the 14th member of the MAP kinase kinase kinase (MAP3K) family, and IKKα (see Figure 2B) to determine the liberation of p52-RelB protein complexes (see Figure 1; References [1–5]). The indication and identification of NIK as the first major regulatory component of the non- canonical NF-κB pathway came from studies upon alymphoplasia (aly/aly) mice that display an amino acid substitution (G886R) in the NIK protein structure [8–11]. These mice showed phenotypic similarities with those with deficiencies or mutations in NF-κB2/p100 (see Reference [1]). Aly/aly mice were characterised as displaying low levels of
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