Biomarkers associated with LSD1 inhibitors and uses thereof
A biomarker and inhibitor technology, applied in the field of biomarkers, can solve problems such as insufficient identification of PD markers
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Embodiment 1
[1598] Example 1: LSD1 Inhibitors and In Vitro Biochemical Analysis
[1599] This example describes the LSD1 inhibitors used in the subsequent examples and the method for assessing the activity of the test compounds against LSD1 and the related enzymes MAO-A and MAO-B.
[1600]1.1 LSD1 inhibitors used
[1601] Compound 1 is (-)5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazole-2 - Amines, obtainable as disclosed in WO2012 / 013728.
[1602] Compound 2 is an enantiomer of compound 1 and it is compound (+) 5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl) -1,3,4-oxadiazol-2-amine. It can be obtained as disclosed in WO2012 / 013728.
[1603] Compound 3 is a compound having the following chemical name and structure, and is obtainable as disclosed in WO2011 / 042217:
[1604]
[1605] 2-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)acetamide.
[1606] Compound 4 is a compound having the following chemical name and structure, and is ...
Embodiment 2
[1628] Example 2: Gene expression analysis by microarray hybridization
[1629] This example describes the general methodology used to perform microarray gene expression analysis in subsequent examples.
[1630] 2.1 RNA extraction and labeling methods
[1631] Total RNA was extracted from samples using the RNeasy extraction kit (Qiagen). Using Agilent2100 Bioanalyzer and NanoDrop TM ND-1000 (Thermo Scientific) was used to analyze the quality and concentration of RNA. Samples with an RNA Integrity Number (RIN) TM aRNA Amplification Kit (Applied Biosystems), following the manufacturer's instructions (with minor modifications) for total RNA (0.5 μg) amplified and labeled with Cy3 or Cy5. As hybridization controls, plant mRNA was transcribed from plasmids containing the maize (Zea mays) Xet (endo-xyloglucan glycosyltransferase) cDNA and from a plasmid containing the maize Zmmyb42 cDNA using the Eberwein mRNA amplification procedure (as disclosed in Cerda et al. Gen Comp En...
Embodiment 3
[1658] Example 3: S100A8 and S100A9 are up-regulated in SAMP-8 vs. SAMR1 mice while using LSD1 inhibitors Downregulated in the hippocampus of SAMP-8 mice after treatment
[1659] This example demonstrates that S100A8 and most of S100A9 are overexpressed in SAMP-8 mice, a model of accelerated aging and Alzheimer's disease, and that overexpression of these genes can be modulated by treatment with LSD1 inhibitors in the absence of blood significant effect on learning and had a beneficial effect on memory as assessed by the Novel Object Recognition Test (NORT).
[1660] 3.1 Mouse strains and treatments
[1661] The Senescence Accelerated Mouse Prone 8 (SAMP8) strain is a non-transgenic model of neurodegenerative disease (T Takeda, Neurobiol Aging 1999, 20(2):105-10). Memory deficits appear in SAMP8 mice at about 5 months of age and can thus be reliably assessed using the Novel Object Recognition Test (NORT). The rapidly aging mouse resistance 1 (SAMR1) strain showed no memor...
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