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Muscarinic acetylcholine receptor subtype 4 antagonists in the treatment of anemia

An ethyl, solvate technology in the field of muscarinic acetylcholine receptor subtype 4 antagonists for the treatment of anemia

Pending Publication Date: 2021-11-05
COLD SPRING HARBOR LAB INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, many anemic patients do not have sufficient BFU-E and subsequently insufficient CFU-E to respond to EPO treatment (Flygare J. et al., Blood, 117:3435-3444 (2011); Zhang L. et al., Nature , 499:92-96 (2013); Sankaran V.G. et al., Nat Med, 21:221-230 (2015); Bauer et al., Genes Dev, 13:2996-3002 (1999); Komrokji R.S. et al., Curr Hematol Malig Rep, 6:145-153 (2011); Kotla V. et al., Hematol Onco., 2:36 (2009))

Method used

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  • Muscarinic acetylcholine receptor subtype 4 antagonists in the treatment of anemia
  • Muscarinic acetylcholine receptor subtype 4 antagonists in the treatment of anemia
  • Muscarinic acetylcholine receptor subtype 4 antagonists in the treatment of anemia

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0140] This example describes the effect of the muscarinic acetylcholine receptor CHRM4 pathway on the self-renewal of BFU-E and the effect of the small molecule muscarinic acetylcholine receptor inhibitor paraxetonium bromide on anemia in a mouse model. experiment of.

[0141] result

[0142]To identify G protein-coupled receptors ("GPCRs") that regulate BFU-E self-renewal, genome-wide gene expression profiles were analyzed, focusing on GPCRs that are abundantly expressed in BFU-E. To further narrow down the candidate list to the GPCRs most likely to be functionally important in the regulation of BFU-E self-renewal versus differentiation, the inventors took advantage of the fact that differentiation and self-renewal are two opposites with potentially contrasting gene expression profiles. The concept of cell fate.

[0143] Among the 358 druggable GPCRs examined, 3 GPCRs including P2ry2, Gpr124 and Calcrl were found to be downregulated during BFU-E differentiation and upregul...

Embodiment -2

[0176] This example describes experiments performed to investigate whether other small molecule M4 antagonists, such as PCS1055 and PD102807, promote BFU-E self-renewal and correct anemia in vivo.

[0177] result

[0178] Figure 4A shows the chemical structure of PD102807. PD102807 was found to increase the expansion of BFU-E cells in cell culture (Fig. 4B). In addition, PD102807 was also found to increase the levels of HCT and RBC when administered to mice (PD102807 was given intravenously or orally) (see Figures 4C and 4D, respectively). Figure 4E shows that at 1 × 10 -9 M, 1×10 -8 M, 1×10 -7 M, 1×10 -6 M and 1×10 -5 Results of testing PD102807 at M concentrations.

[0179] Materials and methods

[0180] Mouse BFU-E Culture System

[0181] BFU-E was isolated from mouse embryonic day 14.5 fetal liver using fluorescence-activated cell sorting (FACS). BFU-E in StemSpan SFEM II containing rmSCF (100ng / ml), EPO (2U / ml), rmIGF-1 (40ng / ml), dexamethasone (1nM) and DMSO, P...

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Abstract

The disclosure generally relates to treating anemias. More specifically, the disclosure relates to use of muscarinic acetylcholine receptor subtype 4 antagonists, such as small molecule compounds, to promote self-renewal of burst forming unit erythroid (BFU-E) cells and treat anemias.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Application No. 62 / 823,214, filed March 25, 2019, the entire contents of which are incorporated herein by reference. [0003] Statement Regarding Federally Funded Research [0004] This invention was made with government support under HL127522 awarded by the National Institutes of Health. The government has certain rights in this invention. technical field [0005] The present disclosure generally relates to the treatment of diseases and disorders caused by muscarinic acetylcholine receptor subtype 4 (M4) activity. More specifically, the present disclosure relates to the use of small molecule M4 antagonist compounds that promote burst erythroid forming unit (BFU-E) cell self-renewal for the treatment of anemia. Background technique [0006] Stem and progenitor cells of many adult lineages undergo self-renewal, a key aspect of tissue homeostasis, maintenance and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/404A61K31/4725A61P7/06A61P25/00
CPCA61P25/00A61K31/4725A61P7/06A61K31/5365C07D401/06C07D498/14
Inventor Y·阿尔阿贝L·张
Owner COLD SPRING HARBOR LAB INC
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