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Substituted azole derivatives for generation, proliferation and differentiation of hematopoietic stem and progenitor cells

A technology for hematopoietic stem cells and peripheral blood stem cells, applied in the field of substituted azole derivatives for the generation, proliferation and differentiation of hematopoietic stem cells and progenitor cells, capable of solving the problem of opportunistic microbial and viral infections that increase whole blood cell reduction receptors Risk and other issues

Active Publication Date: 2019-06-14
NAT UNIV OF SINGAPORE +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Severe delay in hematopoietic reconstitution increases the risk of opportunistic microbial and viral infections in pancytopenic recipients, thus leading to high (>30%) transplant-related mortality (TRM) after UCBT [Bari S et al, Biol Blood Marrow Transplant 21 (6):1008-19(2015); Hofmeister CC et al., Bone Marrow Transplant 39(1):11-23(2007)]

Method used

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  • Substituted azole derivatives for generation, proliferation and differentiation of hematopoietic stem and progenitor cells
  • Substituted azole derivatives for generation, proliferation and differentiation of hematopoietic stem and progenitor cells
  • Substituted azole derivatives for generation, proliferation and differentiation of hematopoietic stem and progenitor cells

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Experimental program
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Effect test

Embodiment 1

[0241] method

[0242] UCB collection, processing, thawing and inoculation

[0243] UCB were obtained from donor units (not meeting clinical storage criteria) through the Singapore Cord Blood Bank (SCBB). The donor mothers and the Research Advisory Ethics Committee of the SCBB and the Institutional Review Boards of the National University of Singapore (NUS) and the Singapore General Hospital (SGH) were consulted in advance. Agreed, the use of the sample is approved. Using Ficoll-Histopaque TM Premium (GE Healthcare, UK) isolated mononuclear cells (MNC) from fresh UCB by density gradient centrifugation. Enumerated UCB-MNCs were cryopreserved in 90% v / v autologous plasma containing 10% v / v dimethylsulfoxide (DMSO) (Sigma Aldrich, USA) for subsequent use. A brief summary of the method is as follows image 3 shown. UCB-MNCs were thawed using human serum albumin (25% v / v) (HealthSciences Authority, Singapore) and Dextran 40 (75% v / v) (Hospira, USA). UCB-MNC empirically deter...

Embodiment 2

[0268] Main method steps

[0269] In an embodiment of the present invention, the main steps involved in the method of using IM-29 to amplify HSPC from freeze-thawed UCB-MNC are as follows: figure 2 Shown:

[0270] (i) Fresh UCB was processed using density-dependent centrifugation to isolate the mononuclear (MNC) fraction, which was frozen at -180°C for future expansion;

[0271] (ii) thawing and culturing UCB-MNCs in a defined medium containing a cytokine mixture of SCF, TPO, FLT-3L and IGFBP-2;

[0272] (iii) adding IM-29 with a final concentration of 5.0 μM;

[0273] (iv) Keep the cells at 37°C and 5% CO 2 Incubated in a humidified incubator;

[0274] (v) On day 3, the viability of CD45 expressing white blood cells (WBC) was monitored. HSPCs are a subset of CD45 cells;

[0275] (vi) On day 7, supplement (replenish) growth medium, cytokines and IM-29;

[0276] (vii) On day 10 / 11, cells were harvested for assessment of cell expansion by in vitro phenotypic and function...

Embodiment 3

[0279] Small molecules derived from compound SB203580

[0280] The small molecule library includes several analogs, all of which are derived from the parent compound SB203580 ( Figure 6D ), which is a known inhibitor of p38MAPK (mitogen-activated protein kinase) with optimal activity at working concentrations of 5 to 10 μΜ. have Figure 6A Compound IM-29 of the shown chemical structure was the most potent of the compounds tested. have Figure 6B IM-04 of the shown chemical structure was the second most potent compound. Structural analogs of IM-29 and IM-04 that gave suboptimal effects are shown in Figure 6C middle. A total of 40 SB203580 analogs were generated for this study, which are shown in Figure 6E , and are roughly divided into four groups based on structure and chemical modification. Figure 6E Group 1 examined changes in the substituent at the C-2 position of the imidazole while retaining the pyridin-4-yl / 3-tolyl or pyridin-4-yl / 3 -(trifluoromethyl)phenyl m...

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Abstract

The present invention relates to substituted azole derivatives and their use in the ex vivo expansion of CD34+ hematopoietic stem and progenitor cells (HSPC) in a biological sample, more particularlyin the expansion of these cells obtained from non-enriched, i.e., the mononuclear fraction of the biological sample. The present invention further describes the transplantation regimen of the expandedhematopoietic graft developed through xenotransplantation studies.

Description

technical field [0001] The present invention relates to substituted azole derivatives and their use for the ex vivo expansion of CD34-expressing hematopoietic stem and progenitor cells (HSPCs) in biological samples; more particularly, the expansion of mononuclear cells from non-enriched, i.e. Fractions of these cells were obtained. The present invention further describes transplantation protocols for expanded hematopoietic grafts developed through xenotransplantation studies. Background technique [0002] Hematopoietic stem cell transplantation (HSCT) is used to correct blood cell defects leading to malignant and benign diseases by replacing diseased blood cells with healthy donor cells [Gratwohl A et al., JAMA 303(16):1617-1624 (2010)]. To date, more than one million HSCTs have been performed using mobilized peripheral blood stem cells (PBSC), bone marrow (BM) and umbilical cord blood (UCB) as the source of grafts. The number of registered HSCTs has tripled in the past de...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04C07D413/04A61K35/28A61K35/51C12N5/0789A61P7/06A61P37/00
CPCA61P7/06A61P37/00A61K35/00C12N5/0647C12N2501/999A61K35/28A61K35/51C12N2501/105C12N2501/125C12N2501/145C12N2501/26
Inventor S·巴里C·L·L·蔡G·N·C·邱W·Y·K·黄J·L·刘Q·钟
Owner NAT UNIV OF SINGAPORE
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