Compositions and methods relating to novel benzodiazepine compounds and targets thereof
AssigneeThe Regents of the University of Michigan
InventorsGary D. Glick, Anthony W. Opipari
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Abstract
The present invention relates to novel chemical compounds, methods for their discovery, and their therapeutic use. In particular, the present invention provides benzodiazepine derivatives and methods of using benzodiazepine derivatives as therapeutic agents to treat a number of conditions associated with the faulty regulation of the processes of programmed cell death, autoimmunity, inflammation, and hyperproliferation, and the like.
Claims53
A method for regulating cell death comprising:
- a. providing:
- i. target cells having mitochondria;
- ii. an agent that binds to oligomycin sensitivity conferring protein;
- and
- b. exposing said cells to said agent under conditions such that said agent binds to said oligomycin sensitivity conferring protein so as to increase superoxide levels or alter cellular ATP levels in said cells.
A method for inhibiting proliferation in cells comprising:
- a. providing:
- i. proliferating target cells having mitochondria;
- ii. an agent that binds to mitochondrial ATP synthase complex;
- and
- b. exposing said cells to said agent under conditions such that said agent binds to said mitochondrial ATP synthase complex so as to increase superoxide levels or alter cellular ATP levels in said cells.
A pharmaceutical composition comprising:
- a. a sufficient dose of an agent that binds to oligomycin sensitivity conferring protein so as to increase superoxide or alter cellular ATP levels in cells of a subject exposed to said agent;
- and
- b. instructions for using said agent for treating a condition that is ameliorated by initiation of cell death.
A pharmaceutical composition comprising:
- a. a sufficient dose of an agent that binds to mitochondrial ATP synthase complex so as to increase superoxide or alter cellular ATP levels in cells of a subject exposed to said agent;
- and
- b. instructions for using said agent for treating an autoimmune disease, a proliferative disease, or cancer.
A method for identifying agents useful for treating proliferative diseases, autoimmune diseases, or cancer comprising:
- a. providing:
- i. mitochondrial ATP synthase complex;
- ii. benzodiazepine or a benzodione derivative;
- and
- iii. a candidate agent;
- and
- b. exposing said mitochondrial ATP synthase complex to said benzodiazepine or a benzodione derivative and said candidate agent;
- and
- c. comparing the binding of said benzodiazepine or a benzodione derivative and said candidate agent to said mitochondrial ATP synthase complex.
A method for identifying pharmaceutical agents, comprising:
- a. providing an agent that binds to mitochondrial ATP synthase complex so as to generate superoxide free radicals, initiate cell death, or alter cellular proliferation;
- b. chemically modifying said agent to generate a library of candidate pharmaceutical agents;
- and
- c. selecting one or more individual members of said library of candidate agents based on their increased ability to generate superoxide free radicals, initiate cell death, or alter cellular proliferation compared to said agent.
A method for screening for agents that selectively induce cell death or inhibit the growth or proliferation of activated cells, comprising:
- a. providing:
- i. a first cell sample comprising at least one unactivated cell;
- ii. a second cell sample comprising at least one unactivated cell;
- iii. a third cell sample comprising at least one unactivated cell;
- iv. an effective amount of an activating agent;
- v. an effective amount of a candidate agent;
- vi. an effective ratio and amount of said activating agent and said candidate agent;
- and
- b. contacting said first cell sample with said effective amount of said activating agent;
- c. contacting said second cell sample with said effective amount of said candidate agent;
- d. contacting said third cell sample with said effective ratio and amount of said activating agent and said candidate agent;
- e. comparing the level of cell death or cell number in said third cell sample to the level of cell death or cell number in said first cell sample and said second cell sample;
- and
- f. comparing the amount of cell death or growth inhibition in said third cell sample to the level of cell death or growth inhibition in said first cell sample and said second cell sample.
A method for inhibiting induced cell death in an activated target cell by contacting the activated target cell with an effective amount of an agent that inhibits the formation of superoxide in said activated target cell prior to mitochondrial permeability transition.
A method for screening for agents that selectively induce cell death or inhibit the growth or proliferation of activated cells, comprising:
- a. providing:
- i. a first cell sample comprising at least one unactivated cell;
- ii. a second cell sample comprising at least one unactivated cell;
- iii. a candidate agent;
- and
- b. contacting said first cell sample with said candidate agent;
- and
- c. comparing the intracellular concentration of superoxide in first and second cells.
Dependencies are inferred from the claim text.