New Directions in Targeting Protein Kinases: Focusing Upon True Allosteric and Bivalent Inhibitors

Department of Chemistry and Biochemistry, University of Arizona, 1306 East University Blvd, Tucson, AZ 85721, USA.
Current pharmaceutical design (Impact Factor: 3.45). 05/2012; 18(20):2936-45. DOI: 10.2174/138161212800672813
Source: PubMed


Over the past decade, therapeutics that target subsets of the 518 human protein kinases have played a vital role in the fight against cancer. Protein kinases are typically targeted at the adenosine triphosphate (ATP) binding cleft by type I and II inhibitors, however, the high sequence and structural homology shared by protein kinases, especially at the ATP binding site, inherently leads to polypharmacology. In order to discover or design truly selective protein kinase inhibitors as both pharmacological reagents and safer therapeutic leads, new efforts are needed to target kinases outside the ATP cleft. Recent advances include the serendipitous discovery of type III inhibitors that bind a site proximal to the ATP pocket as well as the truly allosteric type IV inhibitors that target protein kinases distal to the substrate binding pocket. These new classes of inhibitors are often selective but usually display moderate affinities. In this review we will discuss the different classes of inhibitors with an emphasis on bisubstrate and bivalent inhibitors (type V) that combine different inhibitor classes. These inhibitors have the potential to couple the high affinity and potency of traditional active site targeted small molecule inhibitors with the selectivity of inhibitors that target the protein kinase surface outside ATP cleft.

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    • "There are different definitions for other types of non-covalent SMKIs, which are referred to as type V inhibitors in this paper. Type V inhibitors include a small group of bivalent or bisubstrate inhibitors (Lamba & Ghosh, 2012; Gower et al., 2014), and a few inhibitors with hybrid type I and II features (Okamoto et al., 2015), which have also been referred to as type 1½ inhibitors (Zuccotto et al., 2010). Even though most allosteric SMKIs are non-ATP competitive, as they bind into a site that does not overlap with the ATP-binding site, some allosteric SMKIs may still be ATP-competitive due to stabilization of the inactive conformation of their binding kinases (Cowan-Jacob et al., 2014). "
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    ABSTRACT: Small-molecule kinase inhibitors are invaluable targeted therapeutics for the treatment of various human diseases, especially cancers. While the majority of approved and developed preclinical small-molecule inhibitors are characterized as type I or type II inhibitors that target the ATP-binding pocket of kinases, the remarkable sequential and structural similarity among ATP pockets renders the selective inhibition of kinases a daunting challenge. Therefore, targeting allosteric pockets of kinases outside the highly conversed ATP pocket has been proposed as a promising alternative to overcome current barriers of kinase inhibitors, including poor selectivity and emergence of drug resistance. In spite of the small number of identified allosteric inhibitors in comparison with that of inhibitors targeting the ATP pocket, encouraging results, such as the FDA-approval of the first small-molecule allosteric inhibitor trametinib in 2013, the progress of more than 10 other allosteric inhibitors in clinical trials, and the emergence of a pipeline of highly selective and potent preclinical molecules, have been reported in the past decade. In this article, we present the current knowledge on allosteric inhibition in terms of conception, classification, potential advantages, and summarized debatable topics in the field. Recent progress and allosteric inhibitors that were identified in the past three years are highlighted in this paper.
    No preview · Article · Oct 2015 · Pharmacology [?] Therapeutics
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    • "Two current approaches to generate selective small molecule kinase inhibitors are the allosteric approach, which involves induction or prevention of enzyme conformational changes via targeting sites outside the catalytic region, and the active site approach [12]–[14]. The allosteric approach is an area of active investigation that has yet to be generally validated or reduced to standard practice. "
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    ABSTRACT: Serine-threonine protein kinases are critical to CNS function, yet there is a dearth of highly selective, CNS-active kinase inhibitors for in vivo investigations. Further, prevailing assumptions raise concerns about whether single kinase inhibitors can show in vivo efficacy for CNS pathologies, and debates over viable approaches to the development of safe and efficacious kinase inhibitors are unsettled. It is critical, therefore, that these scientific challenges be addressed in order to test hypotheses about protein kinases in neuropathology progression and the potential for in vivo modulation of their catalytic activity. Identification of molecular targets whose in vivo modulation can attenuate synaptic dysfunction would provide a foundation for future disease-modifying therapeutic development as well as insight into cellular mechanisms. Clinical and preclinical studies suggest a critical link between synaptic dysfunction in neurodegenerative disorders and the activation of p38αMAPK mediated signaling cascades. Activation in both neurons and glia also offers the unusual potential to generate enhanced responses through targeting a single kinase in two distinct cell types involved in pathology progression. However, target validation has been limited by lack of highly selective inhibitors amenable to in vivo use in the CNS. Therefore, we employed high-resolution co-crystallography and pharmacoinformatics to design and develop a novel synthetic, active site targeted, CNS-active, p38αMAPK inhibitor (MW108). Selectivity was demonstrated by large-scale kinome screens, functional GPCR agonist and antagonist analyses of off-target potential, and evaluation of cellular target engagement. In vitro and in vivo assays demonstrated that MW108 ameliorates beta-amyloid induced synaptic and cognitive dysfunction. A serendipitous discovery during co-crystallographic analyses revised prevailing models about active site targeting of inhibitors, providing insights that will facilitate future kinase inhibitor design. Overall, our studies deliver highly selective in vivo probes appropriate for CNS investigations and demonstrate that modulation of p38αMAPK activity can attenuate synaptic dysfunction.
    Full-text · Article · Jun 2013 · PLoS ONE
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    • "Alternatively, one can expect that stage-, tissue-, and HDAC-specific inhibitors will be developed. A similar approach is now being implemented with respect to protein kinase inhibitors, aimed at treating various diseases, especially cancer (Lamba and Ghosh, 2012). Certainly, use of epigenetic drugs can have multiple and complex effects on different systems and tissues. "

    Full-text · Article · Oct 2012 · Frontiers in Genetics
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