Screening for Small Molecule Disruptors of AKAP–PKA Interactions

Schächterle, Carolin; Frank, Christian; Fernandes, João Miguel Parente; Klussmann, Enno

doi:10.1007/978-1-4939-2537-7_12

Cited by 16 publications

(11 citation statements)

References 17 publications

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“…Small molecule disruptors are another attractive means to pharmacologically target the PKA–AKAP interface. Although these studies are still in their formative stages there have been a few successful attempts at moderate-throughput screening for small molecule AKAP disruptors ( Schachterle et al, 2015 ). Perhaps the most notable example is the development of 3,3′-diamino-4,4′-dihydroxydiphenylmethane (FMP-API-1), a small molecule antagonist that appears to allosterically inhibit the RII–AKAP interaction and activate anchored PKA C-subunit ( Christian et al, 2011 ).…”

Section: Targeting the Pka/akap Interaction For Therapeuticsmentioning

confidence: 99%

Therapeutic strategies for anchored kinases and phosphatases: exploiting short linear motifs and intrinsic disorder

Nygren

Scott

2015

Front. Pharmacol.

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Phosphorylation events that occur in response to the second messenger cAMP are controlled spatially and temporally by protein kinase A (PKA) interacting with A-kinase anchoring proteins (AKAPs). Recent advances in understanding the structural basis for this interaction have reinforced the hypothesis that AKAPs create spatially constrained signaling microdomains. This has led to the realization that the PKA/AKAP interface is a potential drug target for modulating a plethora of cell-signaling events. Pharmacological disruption of kinase–AKAP interactions has previously been explored for disease treatment and remains an interesting area of research. However, disrupting or enhancing the association of phosphatases with AKAPs is a therapeutic concept of equal promise, particularly since they oppose the actions of many anchored kinases. Accordingly, numerous AKAPs bind phosphatases such as protein phosphatase 1 (PP1), calcineurin (PP2B), and PP2A. These multimodal signaling hubs are equally able to control the addition of phosphate groups onto target substrates, as well as the removal of these phosphate groups. In this review, we describe recent advances in structural analysis of kinase and phosphatase interactions with AKAPs, and suggest future possibilities for targeting these interactions for therapeutic benefit.

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Section: Targeting the Pka/akap Interaction For Therapeuticsmentioning

confidence: 99%

Therapeutic strategies for anchored kinases and phosphatases: exploiting short linear motifs and intrinsic disorder

Nygren

Scott

2015

Front. Pharmacol.

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“…In particular, identifying protein-protein interactions that govern the control of AQP2 is relevant as protein-protein interactions are highly specific and diverse and therefore represent a unique class of drug targets. AKAP-PKA interactions that are essential for the AVP-induced redistribution of AQP2 are an example (Christian et al, 2011 ; Schächterle et al, 2015 ). It is important to define “hot spots” within the interacting surfaces, i.e., crucial amino acids that mediate the interaction and that can be targeted with small molecules for effective disruption (Buchwald, 2010 ; Villoutreix et al, 2014 ; Sheng et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

“…Since AKAP-PKA interactions are involved in AQP2 trafficking (Klussmann et al, 1999 ; Klussmann and Rosenthal, 2001 ), their disruption may lead to a new concept for the treatment of diseases characterized by excessive AVP-mediated water retention such as heart failure (Nedvetsky et al, 2009 ; Tröger et al, 2012 ; Deak and Klussmann, 2015 ; Dema et al, 2015 ). Indeed, peptides, peptidomimetics, and small molecules for the non-selective disruption of AKAP-PKA interactions are available (Hundsrucker et al, 2006a , b ; Hundsrucker and Klussmann, 2008 ; Christian et al, 2011 ; Schäfer et al, 2013 ; Schächterle et al, 2015 ). All of these agents target the AKAP-binding domain of regulatory R subunits of PKA, the dimerization/docking (D/D) domain.…”

Section: Pharmacological Targeting Of Protein-protein Interactions Fomentioning

confidence: 99%

The Trafficking of the Water Channel Aquaporin-2 in Renal Principal Cells—a Potential Target for Pharmacological Intervention in Cardiovascular Diseases

et al. 2016

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Arginine-vasopressin (AVP) stimulates the redistribution of water channels, aquaporin-2 (AQP2) from intracellular vesicles into the plasma membrane of renal collecting duct principal cells. By this AVP directs 10% of the water reabsorption from the 170 L of primary urine that the human kidneys produce each day. This review discusses molecular mechanisms underlying the AVP-induced redistribution of AQP2; in particular, it provides an overview over the proteins participating in the control of its localization. Defects preventing the insertion of AQP2 into the plasma membrane cause diabetes insipidus. The disease can be acquired or inherited, and is characterized by polyuria and polydipsia. Vice versa, up-regulation of the system causing a predominant localization of AQP2 in the plasma membrane leads to excessive water retention and hyponatremia as in the syndrome of inappropriate antidiuretic hormone secretion (SIADH), late stage heart failure or liver cirrhosis. This article briefly summarizes the currently available pharmacotherapies for the treatment of such water balance disorders, and discusses the value of newly identified mechanisms controlling AQP2 for developing novel pharmacological strategies. Innovative concepts for the therapy of water balance disorders are required as there is a medical need due to the lack of causal treatments.

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“…It was identified in a high--throughput screen of 20,000 druggable substances. FMP--API--1 allosterically binds RII subunits and thereby blocks AKAP--PKA interactions [36,246]. In addition, PKA is activated upon FMP--API--1 binding.…”

Section: Small Moleculesmentioning

confidence: 99%

Pharmacological Interference With Protein-protein Interactions of Akinase Anchoring Proteins as a Strategy for the Treatment of Disease

Deák¹,

Klussmann

2016

CDT

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A--kinase anchoring proteins (AKAPs) control the localization of cAMP--dependent protein kinase A (PKA) by tethering PKA to distinct cellular compartments. Through additional direct protein--protein interactions with PKA substrates and other signaling molecules they form multi--protein complexes. Thereby, AKAPs regulate the access of PKA to its substrates in a temporal and spatial manner as well as the local crosstalk of cAMP/PKA with other signaling pathways.Due to the increasing information on their molecular functioning and three--dimensional structures, and their emerging roles in the development of diseases, AKAPs move into the focus as potential drug targets. In particular, targeting AKAP--dependent protein--protein interactions for interference with local signal processing inside cells potentially allows for the development of therapeutics with high selectivity and fewer side effects.4

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Screening for Small Molecule Disruptors of AKAP–PKA Interactions

Cited by 16 publications

References 17 publications

Therapeutic strategies for anchored kinases and phosphatases: exploiting short linear motifs and intrinsic disorder

Therapeutic strategies for anchored kinases and phosphatases: exploiting short linear motifs and intrinsic disorder

The Trafficking of the Water Channel Aquaporin-2 in Renal Principal Cells—a Potential Target for Pharmacological Intervention in Cardiovascular Diseases

Pharmacological Interference With Protein-protein Interactions of Akinase Anchoring Proteins as a Strategy for the Treatment of Disease

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