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Compositions and uses thereof

A technology of compounds and polymerases, which can be used in drug combinations, medical preparations containing active ingredients, tripeptide components, etc., can solve problems such as low specific activity and hindering xenograft human cancer in vivo testing

Inactive Publication Date: 2019-05-21
希尔马 M 瓦雷纽斯
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0043] Cyclic peptide THR53, its analogs THR54 (also referred to as HILR-001 in this application) and THR79 (Cyc-[PRGPRPvalklalkalal] (SEQ ID NO: 14) [Warenius et al. Molecular Cancer (2011); 10: 72-88 and WO / 2009 / 112536] selectively kill a wide variety of human cancer cell lines, but have a low specific activity problem, and its IC 50 In the range of 100-200μM
Despite promising anticancer therapeutic potential in vitro, the low specific activity hampers in vivo testing of xenografted human cancers since the required systemic dose would be higher than that tolerated by mice

Method used

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  • Compositions and uses thereof
  • Compositions and uses thereof
  • Compositions and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0372] Example 1: Improved specific activity

[0373]Three cyclic peptides (HILR-001 (SEQ ID NO: 13), HILR-025 (SEQ ID NO: 15) and HILR-030 (SEQ ID NO: 16)) were prepared with >95% purity using conventional automated peptide synthesis techniques . HILR-001 (SEQ ID NO: 13) is a comparative compound prepared according to the literature [Warenius et al, Molecular Cancer (2011); 10:72-88.]. HILR-025 (SEQ ID NO: 15) and HILR-030 (SEQ ID NO: 16) are cyclic compounds comprising (Trp-Trp-Arg-Arg) or (Trp-Trp-Gpa-Gpa) repeat sequences. The activity of the compounds was tested as follows:

[0374] 1) NCI-H460 cells were grown in Ham's F12 medium supplemented with 10% FBS.

[0375] 2) Cells were harvested and seeded into 96-well plates at 500 cells / well.

[0376] 3) Compounds were prepared from stock solutions and added directly to cells at two-fold dilutions starting at 200 μM. The final DMSO concentration was 0.2%.

[0377] 4) Keep cells and compounds at 37°C, 5% CO 2 , grown ...

Embodiment 2

[0384] Example 2: PARP-dependent cytotoxicity

[0385] The present inventors hypothesized that modulation of PARP activity by the PRGPRP cyclic peptide may at least partially contribute to ATP decline and subsequent necrosis in human NSCLC. Thus the HILRa cyclic peptide may be PARP-dependent. If yes, it is assumed that it should be reversed by a PARP inhibitor such as Olaparib.

[0386] In this case, Olaparib will reduce / prevent cell death induced by HILRa cyclic peptide.

[0387] A study was therefore performed to examine the presence of HILR-001 [cyc-(Pro-Arg-Gly-Pro-Arg-Pro-Val-Ala-Lue-Lys-Leu-Ala-Leu-Lys-Leu-Ala-Leu] (SEQ ID NO: 13) (PolypeptideLaboratories, France, SAS, 7 Rue de Boulogne, 67100, Strasbourg, France)] (alone or co-cultivated with Olaparib) exposed for 72 hours and 96 hours, on NCI-H460 human non-small cell Effects of ATP levels and cell death in lung cancer cells.

[0388] The in vitro PARP standard curve was initially generated [ Figure 5 ].

[03...

Embodiment 3

[0426] Example 3: Competitive inhibition of DEVD

[0427] PARP activity is controlled by the presence or absence of cleavage at the DEVD site. Cleaved PARP is inactive with respect to its poly(ADP-ribose) phosphorylation activity. Poly(ADP-ribose) phosphorylation inhibitors such as olaparib are not expected to have any effect on cleaved PARP. Therefore, it is possible that PRGPRP (SEQ ID NO: 2) acts on intact PARP with an intact DEVD region. Furthermore, it was deduced that the activity of HILR-001 could be explained by PRGPRP (SEQ ID NO: 2) binding to the DEVD region of PARP and thus protecting this region from caspase binding and proteolytic cleavage.

[0428] Irrespective of the general secondary and tertiary conformational orientations of peptide regions, it is noteworthy that the linear alignment of the aspartate anion in the GDEVDG region of PARP (SEQ ID NO: 1) aligns with the cationic arginine very close[ Figure 13 ], and these arginines have been shown to be criti...

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Abstract

The present invention relates to compounds capable of modulating the activity of poly(ADP-ribose) polymerase 1 (PARP-1) and / or lactate dehydrogenase A (LDHA) and uses thereof.

Description

technical field [0001] The present invention relates to compositions useful in the treatment of cancer, and in particular to compounds which selectively induce necrosis of cancer cells accompanied by ATP depletion. Background technique [0002] A major impetus to current anticancer drug development has come from the explosive growth in knowledge of cell surface receptors and positive and negative signal transducers, and has recently been furthered by studies of the genomes of several common human cancers. [Pleasance et al. Nature (2009) 463: 191-196; et al. Science (2006) 314: 268-274; Greenman et al. Nature (2007) 446: 153-158; Jones et al. Science (2008) 321: 1801-1806; Gerlinger et al. (2012) 366: 883-892]. These studies have revealed a large number of genetic mutations, hundreds of which are thought to be driver mutations in key proteins involved in signaling pathways that contribute to the evolution of autonomous cancer cell proliferation. [0003] Multiple potentia...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N9/10C07K7/64
CPCA61K38/00A61K45/06C12N9/12A61K31/7004A61P35/00A61K38/06A61K2300/00
Inventor 希尔马·M·瓦雷纽斯
Owner 希尔马 M 瓦雷纽斯
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