Small molecule histone methyltransferase SUV39H1 inhibitor and uses thereof

1. A compound defined according to formula (I) as follows:

where:

R 1 and R 4 are each independently selected from —H, halogen, —NO 2 , —O-alkyl, —N-alkyl, —S-alkyl, —NH 2 , —COO—(C 1 -C 16 )-alkyl, or CONR 5 R 6 ,

R 2 is selected from —H, halogen, —O-alkyl, —N-alkyl, —S-alkyl, —(C 1 -C 33 )-alkyl, -heteroaryl, -aryl, -acyl, or —COO—(C 1 -C 16 )-alkyl,

X is —CH or —N,

Z is selected from —SO 2 , —SO, —(C 1 -C 33 ) alkyl, —(C 1 -C 33 ) alkenyl, C(O)OCH2, —O, or S—S,

Y is selected from —C═O—C═O, —(C 1 -C 4 )-alkyl, —CH═CH—, —O, —S, or —CH 2 R 7 CH 2 ,

R 5 and R 6 are each independently selected from —H, —(C 1 -C 4 )-alkyl, —(C 1 -C 3 )-alkoxy-(C 2 -C 4 )-alkyl, or OH—(C 2 -C 4 )-alkyl,

R 7 is —S, or —O, and n is 1 to 33.

2. The compound of claim 1 , wherein:

R 1 and R 4 are each independently selected from —H, —F, —Cl, —Br, —I, —NO 2 , —O—(C 1 -C 20 )-alkyl, —N—(C 1 -C 20 )-alkyl, —S—(C 1 -C 20 )-alkyl, —NH 2 , —COO—(C 1 -C 16 )-alkyl, or —CONR 5 R 6 , where R 5 and R 6 are each independently selected from —H, —(C 1 -C 4 )-alkyl, —(C 1 -C 3 )-alkoxy-(C 2 -C 4 )-alkyl, or —OH—(C 2 -C 4 )-alkyl,

R 2 is selected from —H, —F, —Cl, —Br, —I, —O—(C 1 -C 20 )-alkyl, —N—(C 1 -C 20 )-alkyl, —S—(C 1 -C 20 )-alkyl, —(C 1 -C 20 )-alkyl, —(C 3 -C 20 )-heteroaryl, —(C 6 -C 20 )-aryl, acyl, or —COO—(C 1 -C 12 )-alkyl,

X is —CH or —N,

Z is selected from —SO 2 , —SO, —(C 1 -C 20 ) alkyl, —(C 1 -C 20 ) alkenyl, C(O)OCH2, —O, — or —SS, where n is 1 to 20, and

Y is selected from —C═O—C═O, —(C 1 -C 3 )-alkyl, —CH═CH—, [—N], —O, —S, —CH 2 SCH 2 , —CH 2 OCH 2 , or —CH 2 NCH 2 .

3. The compound of claim 1 , wherein:

R 1 and R 4 are each independently be selected from —H, —F, —Cl, —NO 2 , —O—(C 1 -C 12 )-alkyl, —N—(C 1 -C 12 )-alkyl, —S—(C 1 -C 12 )-alkyl, —NH 2 , or —COO—(C 1 -C 12 )-alkyl,

R 2 is selected from —H, —F, —Cl, —Br, —I, —O—(C 1 -C 12 )-alkyl, —N—(C 1 -C 12 )-alkyl, —S—(C 1 -C 12 )-alkyl, —(C 1 -C 12 )-alkyl, —(C 3 -C 14 )-heteroaryl, —(C 6 -C 14 )-aryl, R y —CO— where R y is a —(C 1 -C 12 )-alkyl, —(C 3 -C 6 )-cycloalkyl, or phenyl, or —COO—(C 1 -C 4 )-alkyl,

X is —CH or —N,

Z is selected from —SO 2 , —SO, —(C 1 -C 12 ) alkyl, —(C 1 -C 12 ) alkenyl, C(O)OCH2, or —O, where n is 1 to 12, and

Y is selected from —C═O—C═O, —(C 1 -C 2 )-alkyl, or —CH═CH—.

4. The compound of claim 1 , having the following structure:

5. A pharmaceutical composition, comprising:

the compound of claim 1 ,

a hydrate or pharmaceutically acceptable salt, or

any combination thereof.

6. The pharmaceutical composition of claim 5 , wherein the compound is present in an amount effective to inhibit SUV39H1 methyltransferase activity and induce or increase Fas receptor expression on cancer cells.

7. The pharmaceutical composition of claim 5 , further comprising a pharmaceutically acceptable excipient.

8. The pharmaceutical composition of claim 5 , wherein the composition is formulated for parenteral administration.

9. The pharmaceutical composition of claim 8 , wherein the composition is formulated for parenteral administration selected from the group consisting of intramuscular, intraperitoneal, intravitreal, intravenous, and subcutaneous administration.

10. The pharmaceutical composition of claim 5 , wherein the composition is formulated for enteral administration.

11. The pharmaceutical composition of claim 5 , wherein the composition is formulated as an extended release formulation.

12. The pharmaceutical composition of claim 5 , further comprising an effective amount of an anti-PD-1 or anti-PD-L1 immunotherapy.

13. The pharmaceutical composition of claim 12 , wherein the compound is 1-Benzyl 7-methyl 6-(4-chlorobenzenesulfonyl)-4,5-dioxo-3H,4H,5H,6H-pyrrolo[3,2-e]indole-1,7-dicarboxylate.

14. The pharmaceutical composition of claim 5 , further comprising an effective amount of a chemotherapeutic agent.

15. The pharmaceutical composition of claim 5 , wherein the composition comprises the compound having the following structure:

or an enantiomer, hydrate, pharmaceutically acceptable salt, stereoisomer, tautomer, or derivative thereof.

16. A method of treating cancer in a subject having cancer, comprising:

administering to the subject an effective amount of the pharmaceutical composition of claim 5 to increase apoptosis of cancer or tumor cells in the subject.

17. The method of claim 16 , wherein the cancer is colorectal cancer or pancreatic cancer.

18. The method of claim 16 , further comprising administering to the subject an effective amount of a chemotherapeutic agent or an anti-PD-1/PD-L1 immunotherapy in combination or alternation with the pharmaceutical composition of claim 5 .