Treating and preventing diseases by modulating cell mechanics

Patent metadata

Field	Value
Publication number	US-11834401-B2
Application number	US-202016921318-A
Country	US
Kind code	B2
Filing date	Jul 6, 2020
Priority date	Dec 16, 2013
Publication date	Dec 5, 2023
Grant date	Dec 5, 2023

Abstract

Described are methods of treating or preventing a disease in a subject treatable by modulating cell mechanics. The method includes administering to a subject having or at risk for such a disease a pharmaceutical composition. comprising an agent selected from the group comprising a salt, solvate, or stereoisomer of compound (VIII) or its derivatives or a mixture of their constituents, where the compound has the formula:

First claim

We claim:

1. A method for modulating cell mechanics in a disease cell that expresses nonmuscle myosin IIB, nonmuscle myosin IIC, or a combination thereof in a subject comprising:
administering to the subject, an effective amount of a pharmaceutical composition comprising an effective amount of a compound of 4-hydroxyacetophenone or a salt, solvate, or stereoisomer thereof:
and
modulating cell mechanics in the subject; and
wherein the disease cell is from a pancreatic cancer.

2. The method of claim 1 wherein myosin II is activated in the subject compared to a reference subject that has not been administered the effective amount of the compound.

3. The method of claim 1 , wherein the method of administering is systemic delivery selected from the group consisting of oral, parenteral, intranasal, sublingual, rectal, and transdermal administration.

4. The method of claim 1 , further comprising the step of administering a bioactive agent.

5. The method of claim 4 , wherein the bioactive agent is a compound having a formula:

6. The method of claim 4 , wherein the bioactive agent is a chemotherapy agent.

7. The method of claim 1 wherein the subject has a disease that is treated or prevented by modulating the cell mechanics of the subject.

8. The method of claim 1 wherein the cancer is pancreatic cancer.

9. A method of treating cancer in a subject comprising administering to a subject having cancer that expresses nonmuscle myosin IIB, nonmuscle myosin IIC, or a combination thereof in a subject a pharmaceutical composition comprising an agent selected from the group comprising a salt, solvate or stereoisomer of compound (VIII):

wherein X, Y, and Z can independently be N or C, with the proviso that X, Y, and Z cannot all be N, and wherein R 1 is H, OH, Halo, cyano, nitro, C 1 -C 6 alkyl, carboxy C 1 -C 6 alkyl, dicarboxy C 1 -C 6 alkyl, NR 2 R 3 , wherein R 2 and R 3 are independently represent hydroxy, C 1 to C 10 alkyl, alkylamino, alkenyl, alkynyl, hydroxyalkyl, alkoxy, dialkylamino thioalkyl, thioalkenyl, thioalkynyl, aryloxy, acyloxy, thioacyl, amido, and sulphonamido, and wherein X′ is independently represent H, OH, R 7 , OR 7 , NR 7 R 8 , wherein R 7 and R 8 are independently C 1 -C 6 alkyl, carboxy C 1 -C 6 alkyl, dicarboxy C 1 -C 6 alkyl, aryl, heteroaryl, alkenyl, alkynyl, hydroxyalkyl, alkoxy, dialkylamino thioalkyl, thioalkenyl, thioalkynyl, aryloxy, acyloxy, thioacyl, amido, or sulphonamido; and
activating nonmuscle myosin IIB, nonmuscle myosin IIC, or a combination thereof, and
treating pancreatic in the subject,
the method further comprises the step of administering a bioactive agent having a formula:

10. The method of claim 9 , wherein the bioactive agent comprises a chemotherapy agent.

11. The method of claim 9 wherein the compound of Formula VIII is 4-hydroxyacetophenone.

12. The method of claim 1 wherein the cancer is pancreatic cancer.

13. The method of claim 1 wherein the cancer is pancreatic ductal adenocarcinoma.

14. A method of treating pancreatic cancer in a subject comprising administering to a subject an effective amount of a compound of 4-hydroxyacetophenone or salt, solvate or stereoisomer thereof,
thereby treating the pancreatic cancer in the subject.

15. The method of claim 14 wherein the subject is suffering from pancreatic cancer.

16. The method of claim 14 , wherein the subject is suffering from pancreatic ductal adenocarcinoma.

17. A method for modulating cell mechanics in a disease cell that expresses nonmuscle myosin IIB, nonmuscle myosin IIC, or a combination thereof in a subject comprising:
administering to the subject, an effective amount of a pharmaceutical composition comprising an effective amount of a compound (VIII) or a salt, solvate, or stereoisomer thereof:

wherein X, Y, and Z can independently be N or C, with the proviso that X, Y, and Z cannot all be N, and wherein R 1 is H, OH, halo, cyano, nitro, C 1 -C 6 alkyl, carboxy C 1 -C 6 alkyl, dicarboxy C 1 -C 6 alkyl, NR 2 R 3 , wherein R 2 and R 3 are independently OH, C 1 to C 10 alkyl, alkylamino, alkenyl, alkynyl, hydroxyalkyl, alkoxy, dialkylamino thioalkyl, thioalkenyl, thioalkynyl, aryloxy, acyloxy, thioacyl, amido, and sulphonamido, and wherein X′ is H, OH, R 1 , OR 1 , NR 1 Rs, wherein R 1 and Rs, are independently C 1 -C 6 alkyl, carboxy C 1 -C 6 alkyl, dicarboxy C 1 -C 6 alkyl, aryl, heteroaryl, alkenyl, alkynyl, hydroxyalkyl, alkoxy, dialkylamino thioalkyl, thioalkenyl, thioalkynyl, aryloxy, acyloxy, thioacyl, amido, or sulphonamido;
administering a bioactive agent comprising a compound having a formula:

and
modulating cell mechanics in the subject; and
wherein the disease cell is a cell from a pancreatic cancer.

18. A method of treating a cancer in a subject comprising:
administering to a subject having the cancer that expresses nonmuscle myosin IIB, nonmuscle myosin IIC, or a combination thereof in a subject a pharmaceutical composition comprising an effective amount of a compound (VIII) or a salt, solvate, or stereoisomer thereof:

wherein X, Y, and Z can independently be N or C, with the proviso that X, Y, and Z cannot all be N, and wherein R 1 is H, OH, halo, cyano, nitro, C 1 -C 6 alkyl, carboxy C 1 -C 6 alkyl, dicarboxy C 1 -C 6 alkyl, NR 2 R 3 , wherein R 2 and R 3 are independently OH, C 1 to C 10 alkyl, alkylamino, alkenyl, alkynyl, hydroxyalkyl, alkoxy, dialkylamino thioalkyl, thioalkenyl, thioalkynyl, aryloxy, acyloxy, thioacyl, amido, and sulphonamido, and wherein X′ is H, OH, R 1 , OR 1 , NR 1 Rs, wherein R 1 and Rs, are independently C 1 -C 6 alkyl, carboxy C 1 -C 6 alkyl, dicarboxy C 1 -C 6 alkyl, aryl, heteroaryl, alkenyl, alkynyl, hydroxyalkyl, alkoxy, dialkylamino thioalkyl, thioalkenyl, thioalkynyl, aryloxy, acyloxy, thioacyl, amido, or sulphonamido;
administering a bioactive agent comprising a compound having a formula:

wherein the cancer is pancreatic cancer.

Assignees

• Univ Johns Hopkins

Inventors

• Robinson Douglas
• Surcel Alexandra
• Ng Win Pin
• Freel Meyers Caren L

Classifications

• C07C49/825 Primary

  all hydroxy groups bound to the ring · CPC title

• A61K31/12

  Ketones · CPC title

• A61K31/136 Primary

  having the amino group directly attached to the aromatic ring, e.g. benzeneamine · CPC title

• A61K31/15

  Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) {; Imines (C—N=C)} · CPC title

• A61K31/27

  of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine · CPC title