Pseudokinase drug intervention: a potentially poisoned chalice

Claus, Jeroen; Cameron, Angus J.M.; Parker, Peter J.

doi:10.1042/bst20130078

Cited by 12 publications

(12 citation statements)

References 34 publications

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“…TRB2 mutants will also be critical to confirm whether small molecule compounds that bind to the TRB2 pseudokinase site mimic effects of ATP binding (perhaps acting like conventional pharmacological agonists) or whether they prevent ATP binding and therefore ameliorate TRB2 effects on downstream signalling (fulfilling the role of pharmacological antagonists). As pointed out for ligands that bind to HER3, such binding-mode discrimination is important if compounds are to be exploited for effective blockade of disease-associated signalling outcomes rather than to promote them [97,103–105]. In the context of cancer, where TRB2 overexpression is clearly linked to proliferation and disease through regulation of multiple different signalling pathways [35,101,106,107], a judicious selection of compound classes with the latter phenotypic effects should be sought out for initial evaluation.…”

Section: Discussionmentioning

confidence: 99%

The Tribbles 2 (TRB2) pseudokinase binds to ATP and autophosphorylates in a metal-independent manner

Bailey

Byrne

Oruganty

et al. 2015

Biochemical Journal

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The human Tribbles (TRB)-related pseudokinases are CAMK (calcium/calmodulin-dependent protein kinase)-related family members that have evolved a series of highly unusual motifs in the ‘pseudocatalytic’ domain. In canonical kinases, conserved amino acids bind to divalent metal ions and align ATP prior to efficient phosphoryl-transfer to substrates. However, in pseudokinases, atypical residues give rise to diverse and often unstudied biochemical and structural features that are thought to be central to cellular functions. TRB proteins play a crucial role in multiple signalling networks and overexpression confers cancer phenotypes on human cells, marking TRB pseudokinases out as a novel class of drug target. In the present paper, we report that the human pseudokinase TRB2 retains the ability to both bind and hydrolyse ATP weakly in vitro. Kinase activity is metal-independent and involves a catalytic lysine residue, which is conserved in TRB proteins throughout evolution alongside several unique amino acids in the active site. A similar low level of autophosphorylation is also preserved in the closely related human TRB3. By employing chemical genetics, we establish that the nucleotide-binding site of an ‘analogue-sensitive’ (AS) TRB2 mutant can be targeted with specific bulky ligands of the pyrazolo-pyrimidine (PP) chemotype. Our analysis confirms that TRB2 retains low levels of ATP binding and/or catalysis that is targetable with small molecules. Given the significant clinical successes associated with targeting of cancer-associated kinases with small molecule inhibitors, it is likely that similar approaches will be useful for further evaluating the TRB pseudokinases, with the translation of this information likely to furnish new leads for drug discovery.

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Section: Discussionmentioning

confidence: 99%

The Tribbles 2 (TRB2) pseudokinase binds to ATP and autophosphorylates in a metal-independent manner

Bailey

Byrne

Oruganty

et al. 2015

Biochemical Journal

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“…kinases [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22], the latter field likely to mushroom with the development of new tools to study this most experimentally challenging of amino acid modifications [23,24]. The review articles that follow in this issue of Biochemical Society Transactions are contributions from key participants at the meeting, and contain a wealth of new information relevant to devotees of cell signalling.…”

Section: The Pioneers Of Kinome Exploration Set Sailmentioning

confidence: 97%

“…The recent identification of catalytic activity among pseudokinase domains that are mutated in human disease, including the JAK family [16,17] and HER3/ErbB3 [7,11,27], raise the prospect of targeting these and other pseudokinases with specific small molecules in a manner akin to the clinically successful targeting of protein kinases. Intriguingly, as discussed in [7], it remains unclear how important any 'weak' catalytic activity of pseudokinases is with respect to in vivo functions, and naturally leads to the question of whether ATP-mimetic small molecules could modulate the cellular functions of these domains by modulating conformation.…”

Section: Pseudokinases As Drug Targetsmentioning

confidence: 99%

Dawn of the dead: protein pseudokinases signal new adventures in cell biology

Eyers

Murphy

2013

Biochemical Society Transactions

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Recent studies of proteins containing kinase-like domains that lack catalytic residue(s) classically required for phosphotransfer, termed pseudokinases, have uncovered important roles in cell signalling across the kingdoms of life. Additionally, mutations within pseudokinase domains are known to underlie human diseases, suggesting that these proteins may represent new and unexplored therapeutic targets. To date, few pseudokinases have been studied in intricate detail, but as described in the present article and in the subsequent papers in this issue of Biochemical Society Transactions, several new studies have provided an advanced template and an improved framework for interrogating the roles of pseudokinases in signal transduction. In the present article, we review landmarks in the establishment of this field of study, highlight some experimental challenges and propose a simple scheme for definition of these domains based on their primary sequences, rather than experimentally defined nucleotide-binding or catalytic activities.

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“…Jura and colleagues used this information to demonstrate that, despite the smallinhibitor binding to HER3, the process of binding did not inhibit transactivation of EGFR by HER3 [39]. Instead, the 'inhibitor' was actually an activating ligand and increased the binding affinity of the two dimer constituents [39], demonstrating that, depending on their binding mode and changes induced in their target, small molecules can serve as allosteric activators or inhibitors of pseudokinases [40]. This is a general issue that needs to be assessed on a case-by-case basis for all human pseudokinases that probably use combinations of binding to nucleotides, metals or pseudosubstrates as part of their molecular signalling switch mechanism.…”

Section: Her3mentioning

confidence: 99%

Going for broke: targeting the human cancer pseudokinome

Bailey

Byrne

McSkimming

et al. 2015

Biochemical Journal

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Protein phosphorylation lies at the heart of cell signalling, and somatic mutation(s) in kinases drives and sustains a multitude of human diseases, including cancer. The human protein kinase superfamily (the kinome) encodes approximately 50 'pseudokinases', which were initially predicted to be incapable of dynamic cell signalling when compared with canonical enzymatically active kinases. This assumption was supported by bioinformatics, which showed that amino acid changes at one or more key loci, making up the nucleotide-binding site or phosphotransferase machinery, were conserved in multiple vertebrate and non-vertebrate pseudokinase homologues. Protein kinases are highly attractive targets for drug discovery, as evidenced by the approval of almost 30 kinase inhibitors in oncology, and the successful development of the dual JAK1/2 (Janus kinase 1/2) inhibitor ruxolitinib for inflammatory indications. However, for such a large (>550) protein family, a remarkable number have still not been analysed at the molecular level, and only a surprisingly small percentage of kinases have been successfully targeted clinically. This is despite evidence that many are potential candidates for the development of new therapeutics. Indeed, several recent reports confirm that disease-associated pseudokinases can bind to nucleotide co-factors at concentrations achievable in the cell. Together, these findings suggest that drug targeting using either ATP-site or unbiased ligand-discovery approaches should now be attempted using the validation technology currently employed to evaluate their classic protein kinase counterparts. In the present review, we discuss members of the human pseudokinome repertoire, and catalogue somatic amino acid pseudokinase mutations that are emerging as the depth and clinical coverage of the human cancer pseudokinome expand.

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Pseudokinase drug intervention: a potentially poisoned chalice

Cited by 12 publications

References 34 publications

The Tribbles 2 (TRB2) pseudokinase binds to ATP and autophosphorylates in a metal-independent manner

The Tribbles 2 (TRB2) pseudokinase binds to ATP and autophosphorylates in a metal-independent manner

Dawn of the dead: protein pseudokinases signal new adventures in cell biology

Going for broke: targeting the human cancer pseudokinome

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