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Hematopoietic protection against chemotherapeutic compounds using selective cyclin-dependent kinase 4/6 inhibitors

A kinase-dependent, cell cycle-dependent technology, applied in the field of hematopoietic protection against chemotherapeutic compounds using selective cyclin-dependent kinase 4/6 inhibitors, which can solve problems such as inability to provide protection and prevent clinical use

Inactive Publication Date: 2011-11-02
THE UNIV OF NORTH CAROLINA AT CHAPEL HILL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Staurosporine has been shown to have no effect on hematopoietic progenitor cells and staurosporine has been shown not to provide protection immediately after exposure to DNA damaging agents
Nonselective kinase inhibition of staurosporine produces significant toxicities (e.g., hyperglycemia) unrelated to its effects on the cell cycle after in vivo administration to mammals, and these toxicities have prevented its clinical use

Method used

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  • Hematopoietic protection against chemotherapeutic compounds using selective cyclin-dependent kinase 4/6 inhibitors
  • Hematopoietic protection against chemotherapeutic compounds using selective cyclin-dependent kinase 4/6 inhibitors
  • Hematopoietic protection against chemotherapeutic compounds using selective cyclin-dependent kinase 4/6 inhibitors

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0255] Synthetic PD

[0256]

[0257] Route 1: Synthetic PD

[0258] PD was synthesized as shown in Scheme 1 above. The reactions shown in Scheme 1 were carried out essentially as previously reported, except for the conversion of Compound D to Compound E and the reaction of Compound F to Compound G (see VandelWel et al., J. Med Chem., 48, 2371-2387 (2005); and Toogood et al., J. Med. Chem., 48, 2388-2406 (2005)).

[0259] Compound D is converted to Compound E :

[0260]

[0261] Compound D (40 g, 169 mmol) was dissolved in anhydrous THF (800 mL) under nitrogen and the solution was cooled in an ice bath, to which MeMgBr (160 mL, 480 mmol, 3M in ether) was added slowly and stirred for 1 h. with saturated NH 4 The reaction was quenched with aqueous Cl and partitioned between water and EtOAc. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, followed by MgSO 4 dry. Concentration...

Embodiment 2

[0271] Selective G1 arrest in CDK4 / 6-dependent cell lines

[0272] Several human cell lines were exposed to various small molecule kinase inhibitors. Cell cycle analysis was performed as described in the Methods section above.

[0273] After exposure to the potent and selective Cdk4 / 6 inhibitors PD0332991 or 2BrIC, CDK4 / 6-dependent cell lines, including telomerized human diploid fibroblasts (HS68) and the human melanoma cell line WM2664 Shows a pronounced, pure and reversible G1-arrest. see Figure 2A-2E . In addition, less selective CDK inhibitors targeting CDK1 / 2 (e.g. compounds 1-6, flavapine ( Figure 20A ), compound 7 (ie R547; Figure 21A ), Roscovitine ( Figure 22A ), genistein and compounds 8-14 ( Figures 24A-24C )) G2 / M blockade, intra-S-arrest or cell death (sub-G0) variably occurs in these cell types. In contrast, the RB-null melanoma cell line A2058 was insensitive to CDK4 / 6 inhibition, as expected, but, after exposure to less specific CDK inhibitors, s...

Embodiment 3

[0275] Prevention of DNA damage in cells treated with chemotherapeutic agents

[0276] The ability of selective CDK4 / 6 inhibitors to attenuate DNA damage in cells exposed to DNA damaging compounds such as carboplatin, etoposide, and doxorubicin was determined in a cell-based assay as described in the Methods section above . Carboplatin, etoposide, and doxorubicin caused extensive DNA damage as measured by γH2AX foci formation in CDK4 / 6-dependent and CDK4 / 6-independent cell lines. see Figures 3A-3C , 4 and 5. Use PD0332991 ( Figures 6A-6C , 7 and 8) or 2BrIC ( Figures 3A-3C , 4 and 5) Treatment followed by carboplatin, etoposide or doxorubicin attenuated γH2AX staining, suggesting that G1 arrest induced by PD0332991 and 2BrIC protects cells from chemotherapy-induced DNA damage.

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Abstract

Methods for reducing or preventing the effects of cytotoxic compounds in healthy cells are provided. The methods relate to the use of selective cyclin- dependent kinase (CDK) 4 / 6 inhibitors to induce transient quiescence in CDK4 / 6 dependent cells, such as hematopoietic stem cells and / or hematopoietic progenitor cells. Also described is a method of selecting compounds for reducing or preventing the effects of cytotoxic agents compounds in healthy cells.

Description

[0001] related application [0002] The presently disclosed subject matter is based upon and claimed in US Provisional Application 61 / 101,841, filed October 1, 2008; the disclosure of which is incorporated herein by reference in its entirety. [0003] government rights [0004] The subject matter disclosed herein was made with US Government support under Grant Nos. RO1AG024379-01 and K08 CA90679 awarded by the National Institutes of Health through the National Institute on Aging and the National Cancer Institute. Accordingly, the United States Government has certain rights in the subject matter disclosed herein. technical field [0005] The presently disclosed subject matter relates to methods of protecting healthy cells from damage caused by cytotoxic compounds, such as DNA damaging compounds. Specifically, the presently disclosed subject matter relates to cyclin-dependent kinase 4 (CDK4) and / or cyclin-dependent Protective effects of sex kinase 6 (CDK6) inhibitors. [000...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/519A61K31/407A61P35/00
CPCG01N33/5008A61K31/496A61K45/06A61K31/407A61K31/52G01N2333/4739A61K31/4725A61K31/506A61K31/5375A61K31/4738A61K31/453A61K31/4545A61K31/353A61K31/519A61K31/404A61P35/00A61P35/02A61P39/00A61P43/00A61K2300/00
Inventor N·E·沙普尔斯J·C·斯特鲁姆J·E·比希P·J·罗伯茨M·R·拉姆齐
Owner THE UNIV OF NORTH CAROLINA AT CHAPEL HILL
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