Apoptosis related protein in the tgf-beta signaling pathway (ARTS) mimetic compounds, compositions, methods and uses thereof in induction of differentiation and/or apoptosis of premalignant and malignant cells, thereby restoring their normal-like phenotype
View Patent ↗Provided are ARTS mimetic compounds that act as novel antagonists for XIAP and Bcl-2. Further, the novel ARTS mimetic compounds of the presently claimed subject matter induce apoptosis and/or differentiation in premalignant and malignant cells and thereby restore their normal-like phenotype. Further provided are compositions, methods and uses of said ARTS mimetic compounds in the treatment of cancer and premalignant conditions.
1. A method for inducing differentiation and/or apoptosis in a cell, wherein said method comprises the step of contacting said cell with an effective amount of at least one ARTS mimetic compound, any combination thereof any vehicle, matrix, nano- or micro-particle, or any composition comprising said at least one ARTS mimetic compound, wherein said ARTS mimetic compound having the general formula (I) or a pharmaceutically acceptable salt or hydrate thereof or any stereoisomer or salt thereof:
wherein:
R 1 is independently selected from H, C 1 -C 3 alkyl;
R 2 is independently selected from —C(═O)—X—R 3 , —S(═O)—X—R 3′;
X is a heteroatom independently selected from O;
R 3 and R 3′ , independently of each other may be selected independently from H, C 1 -C 3 alkyl;
R 5 is -L1-R 7 -L2-R 8 ;
L1 and L2, independently of each other, are selected independently from —(CH 2 ) n ; —NH—C(═O)—(CH 2 ) n —, —C(═O)—NH—(CH 2 ) n —; —S—S—(CH 2 ) n —; —O—(CH 2 ) n —; —NH—(CH 2 ) n —; C(═O)—(CH 2 ) n —; —S—(CH 2 ) n —; —NH—S(═O) n —(CH 2 ) n —;
n is independently 1 to 3;
R 7 is a carbocyclic ring or a heterocyclic ring;
R 8 is a mono cyclic ring system having 5 to 12, optionally substituted with at least one of OH, CF 3 , halogen, —COOH, —NH 2 , CN, C 1 -C 3 alkyl; and
R 6 is independently selected from H, halogen, CN, NO 2 , C 1 -C 3 alkoxy, straight or branched C 1 -C 3 alkyl.
2. The method according to claim 1 , wherein said ARTS mimetic compound of the general formula (I) is at least one of:
(a) wherein R 1 is H;
(b) wherein R 2 is —C(═O)—X—R 3 ;
(c) wherein X is O;
(d) wherein L1 and L2 independently selected independently from each other from —NH—C(═O)—(CH 2 ) n —, —(CH 2 ) n —; and
(e) wherein R 6 is independently selected from the group consisting of H, halogen, CN, NO 2 .
3. The method according to claim 1 , wherein said ARTS mimetic compound including any stereoisomer or salt thereof having the general formula of:
(a) formula (II)
wherein R 1 , R 2 , R 6 , R 7 , R 8 , L1 and L2 are as defined in claim 1 ; or
(b) formula (III)
wherein R 1 , R 3 , R 6 , R 7 , R 8 , L1 and L2 are as defined in claim 1 ; or
(c) formula (IV)
wherein R 1 , R 2 , R 6 , R 7 , R 8 , and L2 are as defined in claim 1 ; or
(d) formula (VI)
wherein R 1 , R 2 , R 6 , L1 and L2 are as defined in claim 1 .
4. The method according to claim 3 , wherein said compound is 3-[2-(4-Benzyl-piperazin-1-yl)-acetylamino]-5-chloro-1H-indole-2-carboxylic acid methyl ester, having the structure:
including any stereoisomer thereof or salt thereof.
5. The method according to claim 1 , wherein said cell is a premalignant or malignant cell, and wherein said method is for inducing or promoting at least one of: cell differentiation, apicobasal polarization and initiation of lumen formation thereby restoring a normal-like phenotype of a tissue comprising said cell.
6. The method according to claim 5 , for inducing differentiation of pre-malignant or malignant epithelial cell/s.
7. The method according to claim 6 , wherein said cell is any one of a premalignant epithelial breast cell and an epithelial breast carcinoma cell, and wherein said ARTS mimetic compound induces formation of acini-like organoids characterized by a hollow lumen by said epithelial breast cells reminiscent of the normal breast tissue.
8. The method according to claim 5 , wherein said cell is a pre-malignant or malignant epithelial cell in a subject, wherein said method is for inducing differentiation of pre-malignant or malignant epithelial cells in said subject in need thereof, and wherein said contacting is by administering to said subject a therapeutically effective amount of said ARTS mimetic compound.
9. A method for treating, inhibiting, reducing, eliminating, protecting or delaying the onset of a proliferative disorder in a subject in need thereof, said method comprises administering to said subject a therapeutically effective amount of at least one ARTS mimetic compound any vehicle, matrix, nano- or micro-particle or any composition comprising the same, said ARTS mimetic compound having the general formula (I) or a pharmaceutically acceptable salt or hydrate thereof including any stereoisomer thereof
wherein:
R 1 is independently selected from H, C 1 -C 3 alkyl;
R 2 is independently selected from —C(═O)—X—R 3 , —S(═O)—X—R 3′;
X is a heteroatom independently selected from O;
R 3 and R 3′ , independently of each other may be selected independently from H, C 1 -C 3 alkyl;
R 5 is -L1-R 7 -L2-R 8 ;
L1 and L2, independently of each other, are selected independently from —(CH 2 ) n —; —NH—C(═O)—(CH 2 ) n —, —C(═O)—NH—(CH 2 ) n —; —S—S—(CH 2 ) n —; —O—(CH 2 ) n —; —NH—(CH 2 ) n —; C(═O)—(CH 2 ) n —; —S—(CH 2 ) n —; —NH—S(═O) n —(CH 2 ) n —;
n is independently 1 to 3;
R 7 is a carbocyclic ring or a heterocyclic ring;
R 8 is a mono cyclic ring system having 5 to 12 atoms, optionally substituted with at least one of OH, CF 3 , halogen, —COOH, —NH 2 , CN, C 1 -C 3 alkyl; and
R 6 is independently selected from H, halogen, CN, NO 2 , C 1 -C 3 alkoxy, straight or branched C 1 -C 3 alkyl.
10. The method according to claim 9 , wherein said ARTS mimetic compound of the general formula (I) is at least one of:
(a) wherein R 1 is H;
(b) wherein R 2 is —C(═O)—X—R 3 ;
(c) wherein X is O;
(d) wherein L1 and L2 independently selected independently from each other from —NH—C(═O)—(CH 2 ) n —, —(CH 2 ) n —; and
(e) wherein R 6 is independently selected from the group consisting of H, halogen, CN, NO 2 .
11. The method according to claim 9 , wherein said ARTS mimetic compound including any stereoisomer or salt thereof having the general formula of any one of:
(a) formula (II)
wherein R 1 , R 3 , R 6 , R 7 , R 8 , L1 and L2 are as defined herein above;
(b) formula (III)
wherein R 1 , R 3 , R 6 , R 7 , R 8 , L1 and L2 are as defined herein above;
(c) formula (IV)
wherein R 1 , R 2 , R 6 , R 7 , R 8 , and L2 are as defined herein above;
(d) formula (VI)
wherein R 1 , R 2 , R 6 , L1 and L2 are as defined herein above.
12. The method according to claim 11 , wherein said compound is 3-[2-(4-Benzyl-piperazin-1-yl)-acetylamino]-5-chloro-1H-indole-2-carboxylic acid methyl ester, having the structure:
including any stereoisomer or salt thereof.
13. The method according to claim 9 , wherein said subject is a subject suffering from any one of a pre-malignant condition and carcinoma.
14. The method according to claim 13 , wherein said carcinoma is a breast carcinoma.
15. The method according to claim 8 , wherein said subject in need thereof is a subject suffering from a proliferative disorder, and wherein said method is for treating, inhibiting, reducing, eliminating, protecting or delaying the onset of a proliferative disorder in said subject.
16. The method according to claim 1 , wherein said cell is pre-malignant or malignant epithelial cell in a subject, wherein said method is for inducing differentiation of said pre-malignant or malignant epithelial cells in said subject in need thereof, and wherein said contacting is by administering to said subject a therapeutically effective amount of said ARTS mimetic compound.
17. The method according to claim 1 , wherein said cell is pre-malignant or malignant cell in a subject suffering from a proliferative disorder, and wherein said method is for treating, inhibiting, reducing, eliminating, protecting or delaying the onset of a proliferative disorder in said subject in need thereof.
18. The method of claim 1 , wherein the step of contacting the cell comprises administering a therapeutically effective amount of the at least one ARTS mimetic compound or any vehicle, matrix, nano- or micro-particle or any composition comprising the same, the ARTS mimetic compound having the general formula (I) or a pharmaceutically acceptable salt or hydrate thereof to a subject, in need of treating, inhibiting, reducing, eliminating, protecting or delaying the onset of a proliferative disorder, for said treating, inhibiting, reducing, eliminating, protecting or delaying the onset of the proliferative disorder in said subject.