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Phospholipid-FLAGLINE CONJUGATES AND METHODS OF USE THEREOF FOR TARGETED CANCER TREATMENT

A cancer, compound technology, applied in the field of phospholipid-flavagline conjugates

Pending Publication Date: 2022-07-15
SELECTA BIOSCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite their high selectivity, few antibody-drug conjugates are available therapeutically because they achieve only moderate cellular uptake and limited cytocidal activity

Method used

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  • Phospholipid-FLAGLINE CONJUGATES AND METHODS OF USE THEREOF FOR TARGETED CANCER TREATMENT
  • Phospholipid-FLAGLINE CONJUGATES AND METHODS OF USE THEREOF FOR TARGETED CANCER TREATMENT
  • Phospholipid-FLAGLINE CONJUGATES AND METHODS OF USE THEREOF FOR TARGETED CANCER TREATMENT

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0174] chemical synthesis

[0175] PLE. PLE was synthesized according to Scheme 1 below:

[0176]

[0177] plan 1

[0178] Flavagline compounds. Flavagline is commercially available. FLV1 and FLV3 were purchased from Haoyuan Chemexpress Co. (Shanghai, China). FLV1 and FLV3 were alternately synthesized according to Scheme 2 below:

[0179]

[0180]

[0181] Scenario 2

[0182] PLE-flavagline construct. CLR 1852 (compound (9)) and CLR 1865 (compound (8)) were synthesized according to Scheme 3 below:

[0183]

[0184] Scenario 3

[0185] Synthesis of CLR 1899. CLR 1899 was synthesized according to Scheme 4. The structure was verified by NMR and MS data.

[0186]

[0187] Scenario 4

Embodiment 2

[0189] Presence of lipid rafts in tumor cells

[0190] Over 100 cell lines were stained with cholera toxin subunit B, fixed with 4% formaldehyde, and stained with filipin III for 30 minutes. like Figures 1A-1D shown, nearly all tumor types tested showed high lipid raft concentrations in cell membranes (over 100 cell lines, fresh patient samples, etc.). like Figure 1E As indicated, A549 cells were co-cultured with normal fibroblasts for 48 h, then stained with cholera toxin subunit B, fixed with 4% formaldehyde, and stained with filipinIII for 30 min. These results suggest that tumor cells have higher concentrations of lipid rafts than normal cells.

Embodiment 3

[0192] PDC selects for uptake into tumor cells

[0193] Normal fibroblasts and Caki-2 tumor cells (human clear cell renal cell carcinoma) were plated and co-cultured overnight ( Figure 1F ). Cells were then incubated with 5 μM CLR1501 (compound (1)) in complete medium at 37°C for 24 hours. Cells were washed the next day and co-stained with nuclear stain (Hoescht 33342). CLR 1501 was excited and then detected with an Alexa-Fluor 488 filter. CLR 1501 is highly localized in Caki-2 cells and least in normal fibroblasts.

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Abstract

Disclosed herein are phospholipid ether (PLE) molecules. The present invention also provides a phospholipid-flavagline conjugate and a preparation method of the phospholipid-flavagline conjugate. The phospholipid-flavagline conjugate may include a PLE conjugated to a flavagline by a linker, and a method for preparing the same. The phospholipid-flavagline conjugate may include a PLE conjugated to a flavagline by a linker. Also provided herein are methods of treating cancer in a subject and methods of targeting a drug to a tumor or cancer cell in a subject.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This application claims the benefit of and priority to US Provisional Patent Application No. 62 / 913,571, filed October 10, 2019, the contents of which are incorporated herein by reference in their entirety. technical field [0003] The present disclosure relates to phospholipid-flavagline conjugates and targeted cancer therapy. Background technique [0004] The utility of most anticancer drugs in clinical use is limited by their toxicity to all proliferating cells, and / or their inability to act on all tumor cells. Novel agents with unique pharmacological effects are continually being developed, providing enhanced targeting, however, many of these compounds still lack absolute tumor selectivity and continue to limit their therapeutic applications due to off-target effects. Antibody-drug conjugates (ADCs) have been designed to bind to specific epitopes on the tumor cell surface and provide another approach to targeting ...

Claims

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Application Information

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IPC IPC(8): C07D307/93C07D413/04A61P35/00
CPCA61P35/00C07F9/65517A61K31/665
Inventor J·隆科尔
Owner SELECTA BIOSCI
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