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Methods and systems for identifying mechanisms of action of drugs using network dysregulation

A technology of mechanism of action and pharmacological effects, applied in biological systems, biostatistics, bioinformatics, etc., can solve problems that are not suitable for genome-wide analysis and are impractical

Active Publication Date: 2019-11-19
THE TRUSTEES OF COLUMBIA UNIV IN THE CITY OF NEW YORK
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, some methods either rely on prior knowledge of the pathways mediating compound activity, making them unsuitable for genome-wide analysis, or require very large sample sizes (n > 100), thus making them useful even for small compound libraries. unrealistic

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  • Methods and systems for identifying mechanisms of action of drugs using network dysregulation
  • Methods and systems for identifying mechanisms of action of drugs using network dysregulation
  • Methods and systems for identifying mechanisms of action of drugs using network dysregulation

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Experimental program
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Embodiment

[0040] Example: DeMAND

[0041] Given the potential for a candidate gene product G (i.e., its regulator) including transcriptional, signaling, and protein-complex-related interactions interaction, if G belongs to the MoA of the compound, it can be assumed that the activity of the compound will deregulate its regulon. Thus, such dysregulation can be assessed by measuring changes in the joint probability density p(G,G') of gene expression between pairwise regulator interactions. This can capture the direct effect of the compound on the modulation of candidate MoA gene expression and interaction partner expression through direct or indirect regulatory mechanisms (eg, feedback loops).

[0042] For example, consider a candidate MoA gene product G that regulates a set of transcriptional targets. Targeted inhibitors will significantly alter the joint expression probability density of G and its target, since the expression of the latter will be affected, while the expression of G i...

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Abstract

Disclosed herein are techniques for using network dysregulation to identify the mechanism of action of a compound. Exemplary methods can include selecting at least a first interaction involving at least a first gene, determining a first n-dimensional probability density of gene expression levels of the first gene and one or more genes in a control state, determining a probability density in the first n-dimension using at least one a second n-dimensional probability density of the gene expression levels of the first gene and the one or more genes after treatment with the compound, estimating a change between the first probability density and the second probability density, and determining whether the estimated change is Statistically significant.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Application Serial No. 61 / 991,005, filed May 9, 2014, and U.S. Provisional Application Serial No. 62 / 027,045, filed July 21, 2014, which are hereby incorporated by reference in their entirety Application. [0003] Statement Regarding Federally Funded Research [0004] This invention was made with government support under Grant Numbers U01 CA164184, U01 HL 111566, and U54 CA 121852 awarded by the National Institutes of Health (NIH). The government has certain rights in this invention. [0005] Background of the invention [0006] A compound's mechanism of action (MoA) can be defined as the collection of biochemical interactors and effectors by which a compound produces its pharmacological action, which is often specific to the cellular context. MoA can be used in the development of new drugs, understanding side effects of new drugs, and drug repositioning. However, s...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): G16C20/10G16B5/00G16B40/00G16B5/20G16B35/00
CPCG16C20/10G16B5/00G16B40/00G16B5/20G16B35/00G16C20/60
Inventor A·卡利法诺M·班索Y·希莫尼
Owner THE TRUSTEES OF COLUMBIA UNIV IN THE CITY OF NEW YORK