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Methods and systems for screening candidate compounds for their potential to cause systemic or hepatic toxicity

A technology for screening compounds and compounds, applied in the fields of biochemical equipment and methods, microorganisms, biological testing, etc.

Active Publication Date: 2019-07-02
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

NCEs that may cause drug-induced cholestatic hepatotoxicity may not be considered in further drug development trials

Method used

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  • Methods and systems for screening candidate compounds for their potential to cause systemic or hepatic toxicity
  • Methods and systems for screening candidate compounds for their potential to cause systemic or hepatic toxicity
  • Methods and systems for screening candidate compounds for their potential to cause systemic or hepatic toxicity

Examples

Experimental program
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Effect test

Embodiment 1

[0082] bile acid homeostasis

[0083] As demonstrated here, drug-induced cholestatic hepatotoxicity is a consequence of impaired bile acid inhibition of BSEP by NCE and impaired adaptive response of hepatocytes to bile acid homeostasis. A possible mechanism of action causing drug-induced cholestatic hepatotoxicity could include inhibition of cholestatic hepatotoxicity of BSEP function (initial injury) and 1) prevention (antagonism) of farnesoid X receptor (FXR) sensing of bile acid cells or 2) inhibition of all bile acid efflux pathways (basolateral and canalicular); or 3) a combination of both.

[0084] Figure 1A to Figure 6 is a schematic diagram of a hepatocyte system 10 (in vivo or in vitro) comprising hepatocytes 12 having tight junctions 14 and one or more bile canaliculi 16 therebetween. Components, enzymes and transporters in cellular systems include: bile acid BA; adenosine triphosphate ATP; farnesoid X receptor FXR; bile salt export protein BSEP; multidrug resista...

Embodiment 2

[0094] Feedback mechanism of bile acid homeostasis

[0095] figure 2 Normal bile acid uptake (NTCP), synthesis (CYP7A1 ) and export (BSEP) in vivo are exemplified. image 3The effect of NCE as a BSEP inhibitor to initiate feedback mechanisms of bile acid homeostasis (eg activation of FXR) leads to induction of compensatory mechanisms (eg basolateral efflux transporter OSTα / β) and reduction of bile acid intracellular concentrations. Initiation of the bile acid feedback mechanism prevents bile acid hepatotoxicity (aka cholestatic hepatotoxicity). Figure 4 The effects of NCE as BSEP inhibitors and FXR antagonists that prevent activation of the feedback mechanism of bile acid homeostasis, which leads to increased intracellular concentrations of bile acids, leading to bile acid hepatotoxicity (aka cholestatic hepatotoxicity) are exemplified. Figure 5 NCEs that inhibit the action of multiple bile acid efflux pathways, leading to hepatotoxicity, are exemplified. Bile acid feedb...

Embodiment 3

[0097] Development of an assay device for screening hepatotoxicity of cholestasis

[0098] Provided herein are assay devices, methods and systems to identify NCEs that may interfere with the bile acid processing capacity of hepatocytes. In some embodiments, such assays, methods and systems are configured to be based on toxicity assays (e.g. ATP / LDH / caspase 3 / 7 / 8) and / or by monitoring and clinical measurements (AST / ALT )-related LDH links cholestasis to hepatotoxicity, and the AST / ALT is commonly used to monitor liver function. In some embodiments, such assay devices, methods and systems are configured to classify NCE as cholestatic, ineffective, or cholestatic hepatotoxic.

[0099] In some embodiments, the potential outcome (BA in the presence of NCE) can be as follows Figure 7 and Figure 8 expression shown in . exist Figure 7 and Figure 8 In , dotted, dashed, and solid lines indicate the following:

[0100] -Dotted line

[0101] BA dose-appropriate to determine BA...

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Abstract

Methods of screening a compound for susceptibility to causing systemic or hepatic toxicity, using a hepatic cell system exposed to a range of concentrations of a bile acid in the absence or presence of a compound to determine a toxicity profile. In vitro systems for predicting in vivo hepatotoxic potential of a compound are also provided, and include in vitro cultured hepatic cell systems with a capacity for bile acid synthesis, bile acid transport and bile acid regulation.

Description

[0001] References to related applications [0002] This patent application claims priority to U.S. Provisional Patent Application Serial No. 62 / 395,503, filed September 16, 2016, the entire contents of which are incorporated herein by reference. technical field [0003] The present disclosure relates to screening candidate compounds or chemical entities for their potential for cholestatic hepatotoxicity. More specifically, the present disclosure relates to methods and systems for screening candidate compounds that cause or that may cause susceptibility to systemic or hepatotoxicity. Background technique [0004] In the development of novel therapeutic agents, drugs, and drug compounds, novel chemical entities (NCEs) need to be screened for their potential for cholestatic hepatotoxicity. Drug-induced cholestatic hepatotoxicity is the result of impaired bile flow of bile acids leading to accumulation of toxic concentrations of bile acids in hepatocytes. NCEs that may cause d...

Claims

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Application Information

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IPC IPC(8): G01N33/58
CPCG01N33/5014G01N33/5067C12N5/067G01N33/6875G01N2333/4753G01N2333/70567G01N2800/08
Inventor 肯尼思·R·布劳威尔乔纳森·P·杰克逊克里斯托夫弗·B·布拉克
Owner QUALYST TRANSPORTER SOLUTIONS
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