The rational design of allosteric kinase modulators is challenging but rewarding. The protein kinase PDK1, which lies at the center of the growth-factor signaling pathway, possesses an allosteric regulatory site previously validated both in vitro and in cells.ANCHOR.QUERYsoftware was used to discover ap otent allosteric PDK1 kinase modulator.U sing ar ecently published PDK1 compound as at emplate,s everal new scaffolds that bind to the allosteric target site were generated and one example was validated. The inhibitor can be synthesized in one step by multicomponent reaction (MCR) chemistry when using the ANCHOR.QUERYapproach.O ur results are significant because the outlined approach allows rapid and efficient scaffold hopping from knownm olecules into new easily accessible and biologically active ones.B ased on increasing interest in allosteric-site drug discovery,w e foresee many potential applications for this approach.Compounds with an allosteric mode of action enable modulation of the protein function that cannot be accomplished by active-site inhibitors. [1] Additionally,a llosteric receptor sites are often less conserved than active sites in ap rotein family.H ence,m ore selective receptor modulation is possible and often new therapeutic qualities can be accomplished. Fore xample,m ost ATP-competitive kinase inhibitors show limited selectivity,a nd therefore clean and selective regulation of acellular pathway is often prohibited. While nonselective kinase inhibitors were considered advantageous for targeting more than one signaling pathway in cancer, some clinical kinase inhibitors show considerable toxicity owing to polypharmacology.M ore-selective kinase inhibitors are potentially better suited for combination with other selective targeted drugs in future personalized treatments.Asasubgroup of the human kinome,the AGCkinases provide au nique opportunity to discover allosteric modulators since ar egulatory allosteric site,t he so called PIFpocket, is well established. [2] Amongst these kinases,3phosphoinositide-dependent protein kinase-1 (PDK1
Bacteria control the metabolic processes by which they obtain nutrients and energy in order to adapt to the environment. Actinobacteria , one of the largest bacterial phyla of major importance for biotechnology, medicine, and agriculture, developed a unique control process that revolves around a key protein, the protein kinase PknG. Here, we use genetic, biochemical, and structural approaches to study PknG in a system that regulates glutamate production in Corynebacterium glutamicum , a species used for the industrial production of amino acids.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Over the last 20 years, protein kinases have been at the forefront of drug discovery programs in the pharmaceutical industry. Almost all protein kinase inhibitor programs were originally directed to the ATP‐binding site, while more recently allosteric drug developments show improved selectivity. Over the years we investigated the molecular mechanisms of regulation of a large group of kinases, termed AGC kinases (PDK1, PRKs, aPKCs, S6K, SGK, Akt/PKB, RSK, etc.). We identified a regulatory site in the small lobe of PDK1, termed “PIF‐binding pocket” that participates in the docking interaction of PDK1 with a subset of substrates, i.e. S6K, SGK, but not PKB/Akt. In addition, the PIF‐pocket of PDK1 ‐and the equivalent PIF‐pocket site in other AGC kinases‐ participates in the mechanism of activation and inhibition of these kinases, by phosphorylation or interaction with other domains. The binding of synthetic small compounds to the PIF‐pocket can “close” the kinase domain and allosterically “activate” PDK1 in vitro, or allosterically affect the ATP‐binding site and be allosteric inhibitors of other AGC kinases. The present research deals with the studies that describe how the allosteric process, from the regulatory site, to the ATP‐binding site can be “reversed” by small compounds binding to the ATP‐binding site. Thus, different compounds binding with high affinity to the ATP‐binding site can produce different “reverse” allosteric effects on the PIF‐pocket of PDK1, i.e. displace or enhance docking interactions, and ultimately can produce different effects in cell signaling. We now extended the study of the allosterc processes in protein kinases outside of the AGC group of protein kinases. Aurora kinase requires interaction with TPX2 for regulation and localization. We found that binding of VX680 at the ATP‐binding site does not affect interaction with TPX2, while the binding of MLN8237 readily displaces TPX2. Thus, besides inhibition of Aurora catalytic activity, MLN8237 also affects the formation of TPX2/mediated Aurora complexes. PLK1 is autoinhibited by an intramolecular interaction between the Polo‐Box Domain and the catalytic domain. Binding of phosphopeptides to the Polo‐Box Domain displaces the intramolecular interaction and enables full enzymatic activity of the kinase domain in vitro. In addition, the interactions mediated by the Polo‐Box Domain provide localization to the kinase. Upon screening of a library of small molecules, we identified 1‐ small compounds that bind to the ATP‐binding site and enhance the interaction of the Polo‐box domain with phosphopeptides, and small compounds that inhibit the interaction of PLK1 with phosphopeptides, thereby stabilizing the closed inactive conformation and inhibiting protein‐protein interactions. We show that allosteric compounds acting on PLK1 and affecting Polo‐Box Domain interactions are specific inhibitors of PLK1 cellular activity independently of their capacity to inhibit PLK1 catalytic activity. The results highlight the widespread opportunity to modulate kinase cellular activity by exploiting bi‐directional allosteric processes. The old allostery concept can still be exploited for innovative rational drug developments to protein kinases.Support or Funding InformationDFG BI1044 12/1; DFG BI1044 13/1; DKTKThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.