Treating and preventing diseases by modulating cell mechanics

Patent metadata

Field	Value
Publication number	US-2020354301-A1
Application number	US-202016921318-A
Country	US
Kind code	A1
Filing date	Jul 6, 2020
Priority date	Dec 16, 2013
Publication date	Nov 12, 2020
Grant date	—

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

1 .- 10 . (canceled)

11 . 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 the steps of administering to the subject, an effective amount of a pharmaceutical composition comprising a compound of compound (VIII) or or a salt, solvate, or stereoisomer thereof, where the compound has the formula:

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 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, and sulphonamido; and
modulating cell mechanics in the subject.

12 . The method of claim 11 wherein myosin II is activated in the subject compared to a reference subject that has not been administered the effective amount of compound (VIII).

13 . The method of claim 11 , wherein the method of administering is systemic delivery selected from the group consisting of oral, parenteral, intranasal, sublingual, rectal, and transdermal administration.

14 . The method of claim 11 , further comprising the step of administering a bioactive agent.

15 . The method of claim 14 , wherein the bioactive agent is a compound having a formula:

16 . The method of claim 14 , wherein the bioactive agent is a chemotherapy agent.

17 . The method of claim 11 wherein the subject has a disease that is treated or prevented by modulating the cell mechanics of the subject.

18 . The method of claim 17 wherein the disease is cancer.

19 . The method of claim 18 wherein the cancer is pancreas or kidney cancer.

20 .- 31 . (canceled)

32 . 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), where the compound has the formula:

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 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, and sulphonamido;
activating nonmuscle myosin IIB, nonmuscle myosin IIC, or a combination thereof, and treating cancer in the subject.

33 . An in vivo, large-scale and high-throughput screening method for identifying cell mechanical modulator, the screening method comprising the steps of: (a) obtaining cells and placing the cells on multiple-well substrate plates for cytokinesis; (b) contacting the cells on multiple-well substrate plates with compound candidates; and (c) monitoring and analyzing the cytokinesis and the growth of the cells.

34 . The screening method of claim 33 , wherein the cells are from Dictyostelium discoideum strains.

35 . The screening method of claim 34 , wherein Dictyostelium discoideum strains comprise wild type and mutants.

36 . (canceled)

37 . The method of claim 32 , further comprising the step of administering a bioactive agent.

38 . The method of claim 37 , wherein the bioactive agent is a compound having a formula:

39 . The method of claim 37 , wherein the bioactive agent is a chemotherapy agent.

Assignees

• Univ Johns Hopkins

Inventors

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

Classifications

• A61K31/136 Primary

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

• C07C275/30

  being further substituted by halogen atoms, or by nitro or nitroso groups · CPC title

• A61K31/12

  Ketones · CPC title

• C12Q1/025

  for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics (antimicrobial activity C12Q1/18) · CPC title

• A61K31/15

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