Compounds and pharmaceutical compositions for reducing CD95-mediated cell motility
The present invention relates the field of reducing CD95-mediated cell motility in a subject, in particular for their use in the reduction of CD-95 mediated cancer cell motility, the reduction of CD95-mediated lymphocyte motility and/or B cell maturation, or the treatment of B-cell tumors, in a subject. The inventors identified a novel family of compounds having the ability to disrupt CD95/PLCγ1 interaction and to neutralize the CD95-mediated calcium signaling pathway and cell migration in human peripheral blood lymphocytes (PBLs) and Th17 cells. Thus, the present invention relates to compounds of formula (A) as defined in the present text, to a pharmaceutical composition comprising said compounds in a pharmaceutically acceptable medium and to the use of these compounds and compositions as medicament, in particular for their use in the reduction or treatment of the above-mentioned pathologies, and in particular in the treatment of cancers and autoimmune inflammatory disease such as systemic lupus erythematosus, inflammatory condition and Th17-mediated disease.
1. A compound comprising N-acylated-N-aminoethyl amino acids, selected from the group consisting of:
Compound
Structure
Compound 1
Compound 2
Compound 3
Compound 4
Compound 5
Compound 6
Compound 7
Compound 8
Compound 9
Compound 10
Compound 11
Compound 12
Compound 13
Compound 14
Compound 15
Compound 16
Compound 17
Compound 18
Compound 19
Compound 20
Compound 21
Compound 22
Compound 23
Compound 24
Compound 25
Compound 26
Compound 27
Compound 28
Compound 29
Compound 30
Compound 31
or one of its salts;
said compound being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms.
2. The compound according to claim 1 , being selected from formula:
3. The compound according to claim 1 , wherein said compound is grafted with one or several element(s) selected from the group consisting of a reactive moiety; a targeting agent; a dye; a fluorophore; a chemical tag; and an immunomodulating agent.
4. The compound according to claim 3 , wherein the targeting agent is selected from PEG and biotin.
5. The compound according to claim 3 , wherein the dye is a chromophore.
6. The compound according to claim 3 , wherein the fluorophore is selected from rhodamine, fluorescein, BODIPY, indocyanine, and 3,6-bis(1-methyl-4-vinylpyridinium).
7. The compound according to claim 3 , wherein the chemical tag is a ferrocenyl.
8. The compound according to claim 3 , wherein the immunomodulating agent is pomalidomide.
9. The compound according to claim 8 , wherein the pomalidomide comprises a PEG linker.
10. A pharmaceutical composition comprising, in a pharmaceutically acceptable medium, at least one compound according to claim 1 .
11. A method for the reduction of CD95-mediated cell motility in a subject in need thereof comprising the administration to said subject of a compound according to claim 1 , or a composition according to claim 10 .
12. A method for the reduction of CD95 mediated cancer cell motility in a subject in need thereof comprising the administration to said subject of a compound according to claim 1 or a composition according to claim 10 .
13. A method of treatment of cancer in a subject in need thereof, comprising the administration to said subject of a compound according to claim 1 , or a composition according to claim 10 , wherein the subject suffers from a cancer selected from the group consisting of breast cancer, colon cancer, lung cancer, prostate cancer, testicular cancer, brain cancer, skin cancer, rectal cancer, gastric cancer, esophageal cancer, sarcomas, tracheal cancer, head and neck cancer, pancreatic cancer, liver cancer, ovarian cancer, lymphoid cancer, cervical cancer, vulvar cancer, melanoma, mesothelioma, renal cancer, bladder cancer, thyroid cancer, bone cancers, carcinomas, sarcomas, and soft tissue cancers.
14. A method for the reduction of CD95-mediated lymphocyte motility and/or B cell maturation in a subject in need thereof comprising the administration to said subject of a compound according to claim 1 or a composition according to claim 10 .
15. A method for the treatment of an auto-immune inflammatory disease, comprising the administration of a compound according to claim 1 or a composition according to claim 10 .
16. A method for the treatment of systemic lupus erythematosus, comprising the administration of a compound according to claim 1 or a composition according to claim 10 .
17. A method for the treatment of antibody-mediated diseases selected from the list consisting of graft rejection, graft vs. host disease, and inflammatory-autoimmune diseases, comprising the administration of a compound according to claim 1 , or a composition according to claim 10 .
18. A method for treating metastases, comprising the administration of a compound according to claim 1 , or a composition according to claim 10 , in a subject in need thereof.
19. The method according to claim 18 , wherein the subject suffers from a triple negative breast cancer.