Substrate-Selective Inhibition of Protein Kinase PDK1 by Small Compounds that Bind to the PIF-Pocket Allosteric Docking Site

Busschots, Katrien; Lopez-Garcia, Laura A.; Lammi, C.; Stroba, Adriana; Zeuzem, Stefan; Piiper, Albrecht; Alzari, Pedro M.; Neimanis, Sonja; Arencibia, José M.; Engel, Matthias; Schulze, Jörg O.; Biondi, Ricardo M.

doi:10.1016/j.chembiol.2012.07.017

Cited by 72 publications

(97 citation statements)

References 44 publications

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“…Virtual screening, followed by chemical optimization, provided cell active inhibitors of the PDK1/PIF-tide interaction. PS210 (LE= 0.35) mimics two hot-spot phenylalanine residues on the PIF-tide (Busschots et al, 2012). In biochemical assays, this compound activates the kinase towards peptide substrates, as does the PIF-tide.…”

Section: Secondary Structure Epitopes: α-Helix β-Sheet or Extended Pmentioning

confidence: 99%

Small-Molecule Inhibitors of Protein-Protein Interactions: Progressing toward the Reality

Arkin

Tang

Wells

2014

Chemistry & Biology

910

894

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Summary The past twenty years have seen many advances in our understanding of protein-protein interactions (PPI) and how to target them with small-molecule therapeutics. In 2004, we reviewed some early successes; since then, potent inhibitors have been developed for diverse protein complexes, and compounds are now in clinical trials for six targets. Surprisingly, many of these PPI clinical candidates have efficiency metrics typical of ‘lead-like’ or ‘drug-like’ molecules and are orally available. Successful discovery efforts have integrated multiple disciplines and make use of all the modern tools of target-based discovery - structure, computation, screening, and biomarkers. PPI become progressively more challenging as the interfaces become more complex, i.e., as binding epitopes are displayed on primary, secondary, or tertiary structures. Here, we review the last ten years of progress, focusing on the properties of PPI inhibitors that have advanced to clinical trials and prospects for the future of PPI drug discovery.

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Section: Secondary Structure Epitopes: α-Helix β-Sheet or Extended Pmentioning

confidence: 99%

Small-Molecule Inhibitors of Protein-Protein Interactions: Progressing toward the Reality

Arkin

Tang

Wells

2014

Chemistry & Biology

910

894

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“…However, there is evidence that many allosteric inhibitors select for a relatively small number of recurring inactive conformations among kinases. In particular, ligands acting at several known allosteric pockets—including the MEK pocket, the Akt1 pocket, the PIF pocket, and the ANS pocket—have been hypothesized to mediate inactivation through disruption of interactions with a nearby, well-conserved αC-helix (30, 31). Furthermore, both the MEK and PIF pockets have been found in several kinase families and have been shown to induce similar effects across members of the same family (31-33).…”

Section: Therapeutic Targets For Allosteric Modulatorsmentioning

confidence: 99%

Drugs for Allosteric Sites on Receptors

Wenthur

Gentry

Mathews

et al. 2014

Annu. Rev. Pharmacol. Toxicol.

220

272

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The presence of druggable, topographically distinct allosteric sites on a wide range of receptor families has offered new paradigms for small molecules to modulate receptor function. Moreover, ligands that target allosteric sites offer significant advantages over the corresponding orthosteric ligands in terms of selectivity, including subtype selectivity within receptor families, and can also impart improved physicochemical properties. However, allosteric ligands are not a panacea. Many chemical issues (e.g., flat structure-activity relationships) and pharmacological issues (e.g., ligand-biased signaling) that are allosteric centric have emerged. Notably, the fact that allosteric sites are less evolutionarily conserved leads to improved selectivity; however, this can also lead to species differences that can hinder safety assessment. Many allosteric ligands possess molecular switches, wherein a small structural change (chemical or metabolic) can modulate the mode of pharmacology or receptor subtype selectivity. As the field has matured, as described here, key principles and strategies have emerged for the design of ligands/drugs for allosteric sites.

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“…Targeting the allosteric sites on protein kinases may also lead to the identification of activators rather than inhibitors, which could be useful for therapeutic intervention or as pharmacological tools. In particular, compounds targeting the PIF pocket (the hydrophobic motif present in the N-terminal lobe of AGC kinases) of either PDK1 or PKCz can either act as activators (Hindie et al, 2009) or substrate-selective inhibitors (Lopez-Garcia et al, 2011;Sadowsky et al, 2011;Busschots et al, 2012). Similarly, the myr-pocket binders of ABL can be converted into activators if they are designed not to bend helix I of the ABL kinase domain Yang et al, 2011).…”

Section: Downloaded Frommentioning

confidence: 99%

25 Years of Small Molecular Weight Kinase Inhibitors: Potentials and Limitations

2014

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Deregulation of protein and lipid kinase activities leads to a variety of pathologies, ranging from cancer inflammatory diseases, diabetes, infectious diseases, and cardiovascular disorders. Protein kinases and lipid kinases represent, therefore, an important target for the pharmaceutical industry. In fact, approximately one-third of all protein targets under investigation in the pharmaceutical industry are protein or lipid kinases. To date, 30 kinase inhibitors have been approved, which, with few exceptions, are mainly for oncological indications and directed against only a handful of protein and lipid kinases, leaving 70% of the kinome untapped. Despite these successes in kinase drug discovery, the development of kinase inhibitors with outstanding selectivity, identification and validation of driver kinase(s) in diseases, and the emerging problem of resistance to the inhibition of key target kinases remain major challenges. This minireview provides an insight into protein and lipid kinase drug discovery with respect to achievements, binding modes of inhibitors, and novel avenues for the generation of second-generation kinase inhibitors to treat cancers.

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Substrate-Selective Inhibition of Protein Kinase PDK1 by Small Compounds that Bind to the PIF-Pocket Allosteric Docking Site

Cited by 72 publications

References 44 publications

Small-Molecule Inhibitors of Protein-Protein Interactions: Progressing toward the Reality

Small-Molecule Inhibitors of Protein-Protein Interactions: Progressing toward the Reality

Drugs for Allosteric Sites on Receptors

25 Years of Small Molecular Weight Kinase Inhibitors: Potentials and Limitations

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