Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 1. Discovery of a Novel Tool Compound for in Vivo Proof-of-Concept

SummaryBackgroundIncreased circulating plasma urate concentration is associated with an increased risk of coronary heart disease, but the extent of any causative effect of urate on risk of coronary heart disease is still unclear. In this study, we aimed to clarify any causal role of urate on coronary heart disease risk using Mendelian randomisation analysis.MethodsWe first did a fixed-effects meta-analysis of the observational association of plasma urate and risk of coronary heart disease. We then used a conventional Mendelian randomisation approach to investigate the causal relevance using a genetic instrument based on 31 urate-associated single nucleotide polymorphisms (SNPs). To account for potential pleiotropic associations of certain SNPs with risk factors other than urate, we additionally did both a multivariable Mendelian randomisation analysis, in which the genetic associations of SNPs with systolic and diastolic blood pressure, HDL cholesterol, and triglycerides were included as covariates, and an Egger Mendelian randomisation (MR-Egger) analysis to estimate a causal effect accounting for unmeasured pleiotropy.FindingsIn the meta-analysis of 17 prospective observational studies (166 486 individuals; 9784 coronary heart disease events) a 1 SD higher urate concentration was associated with an odds ratio (OR) for coronary heart disease of 1·07 (95% CI 1·04–1·10). The corresponding OR estimates from the conventional, multivariable adjusted, and Egger Mendelian randomisation analysis (58 studies; 198 598 individuals; 65 877 events) were 1·18 (95% CI 1·08–1·29), 1·10 (1·00–1·22), and 1·05 (0·92–1·20), respectively, per 1 SD increment in plasma urate.InterpretationConventional and multivariate Mendelian randomisation analysis implicates a causal role for urate in the development of coronary heart disease, but these estimates might be inflated by hidden pleiotropy. Egger Mendelian randomisation analysis, which accounts for pleiotropy but has less statistical power, suggests there might be no causal effect. These results might help investigators to determine the priority of trials of urate lowering for the prevention of coronary heart disease compared with other potential interventions.FundingUK National Institute for Health Research, British Heart Foundation, and UK Medical Research Council.

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“…The products of two other genes in the instrument ( ABGG2 and GCKR ) were associated with compounds in the early stages of development. 22 …”

Section: Resultsmentioning

confidence: 99%

Plasma urate concentration and risk of coronary heart disease: a Mendelian randomisation analysis

White

Sofat

Hemani

et al. 2016

The Lancet Diabetes & Endocrinology

117

102

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“…The iPPIs dataset (compounds with bioactivity below 30 μM) was built by merging all compounds from IPPI-DB26 minus bromodomain’s inhibitors while adding 89 compounds extracted from the TIMBAL database15 targeting menin-mixed lineage leukemia (MLL) and neuropilin, and 24 small molecule disruptors of the glucokinase–glucokinase regulatory protein interactions142. Regarding the “non-iPPIs” modulators, all datasets were created using the version 14 of the ChEMBL database categorization36 which is available at ftp.ebi.ac.uk/pub/databases/chembl/Allosterism.…”

Section: Methodsmentioning

confidence: 99%

Computational analysis of calculated physicochemical and ADMET properties of protein-protein interaction inhibitors

Lagorce¹,

Douguet²,

Miteva³

et al. 2017

Sci Rep

174

116

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The modulation of PPIs by low molecular weight chemical compounds, particularly by orally bioavailable molecules, would be very valuable in numerous disease indications. However, it is known that PPI inhibitors (iPPIs) tend to have properties that are linked to poor Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) and in some cases to poor clinical outcomes. Previously reported in silico analyses of iPPIs have essentially focused on physicochemical properties but several other ADMET parameters would be important to assess. In order to gain new insights into the ADMET properties of iPPIs, computations were carried out on eight datasets collected from several databases. These datasets involve compounds targeting enzymes, GPCRs, ion channels, nuclear receptors, allosteric modulators, oral marketed drugs, oral natural product-derived marketed drugs and iPPIs. Several trends are reported that should assist the design and optimization of future PPI inhibitors, either for drug discovery endeavors or for chemical biology projects.

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“…It is the search for com pounds inhibiting the GK-GKRP interaction that is currently becoming the major direction in the devel opment of small molecule antidiabetic medications aimed at controlling GK activity. A series of studies by biotechnological company Amgen Inc. (USA) describes the development of drug prototypes [45][46][47][48][49]. In particular, a screening of over 200000 substances performed using high throughput techniques identi fied several compounds that impaired GK-GKRP interaction in vitro [45,46].…”

Section: Small Molecule Compounds Interferingmentioning

confidence: 99%

“…A series of studies by biotechnological company Amgen Inc. (USA) describes the development of drug prototypes [45][46][47][48][49]. In particular, a screening of over 200000 substances performed using high throughput techniques identi fied several compounds that impaired GK-GKRP interaction in vitro [45,46]. The AMG 1694 and AMG 3969 derivatives of these compounds [45][46][47] were shown to normalize glucose levels in several ani mal models of diabetes mellitus and to reverse GK inhibition by GKRP.…”

Section: Small Molecule Compounds Interferingmentioning

confidence: 99%

“…In particular, a screening of over 200000 substances performed using high throughput techniques identi fied several compounds that impaired GK-GKRP interaction in vitro [45,46]. The AMG 1694 and AMG 3969 derivatives of these compounds [45][46][47] were shown to normalize glucose levels in several ani mal models of diabetes mellitus and to reverse GK inhibition by GKRP. They also stimulated GK trans location into the cytoplasm, as shown in isolated rat hepatocytes in vitro and in the liver of Wistar and ZDF rats in vivo [45].…”

Section: Small Molecule Compounds Interferingmentioning

confidence: 99%

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Glucokinase and glucokinase regulatory proteins as molecular targets for novel antidiabetic drugs

2015

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The impairment of glucose homeostasis leads to hyperglycemia and type 2 diabetes mellitus. Glu cokinase (GK), an enzyme that catalyzes the conversion of glucose to glucose 6 phosphate in pancreatic β cells, liver hepatocytes, specific hypothalamic neurons, and intestine enterocytes, is a key regulator of glu cose homeostasis. In hepatocytes, GK controls the glucose uptake and glycogen synthesis and inhibits the glucose synthesis via the gluconeogenesis pathway. Glucokinase regulatory protein (GKRP) synthesized in hepatocytes acts as an endogenous GK inhibitor. During fasting, GKRP binds GK, inactivates it, and trans ports it into the cell nucleus, thus isolating it from the hepatocyte carbohydrate metabolism. In the beginning of the 2000s, the research was mainly focused on the development and trials of the small molecule GK acti vators as potential antidiabetic glucose lowering drugs. However, the use of such substances increased the risk of hypoglycemia, and clinical studies of most synthetic GK activators are currently discontinued. Allosteric inhibitors of the GK-GKRP interaction are coming as alternative agents increasing the GK activity that can substitute GKA. In this review, we discuss the recent advances and the current state of art in the development of potential antidiabetic drugs targeted to GK as a key regulator of glucose homeostasis.

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Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 1. Discovery of a Novel Tool Compound for in Vivo Proof-of-Concept

Cited by 32 publications

References 32 publications

Plasma urate concentration and risk of coronary heart disease: a Mendelian randomisation analysis

Plasma urate concentration and risk of coronary heart disease: a Mendelian randomisation analysis

Computational analysis of calculated physicochemical and ADMET properties of protein-protein interaction inhibitors

Glucokinase and glucokinase regulatory proteins as molecular targets for novel antidiabetic drugs

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