Kinesin motor modulators derived from the marine sponge Adocia
AssigneeThe Regents of the University of California
InventorsLawrence S.B. Goldstein, David John Faulkner, Roman Sakowicz, Michael S. Berdelis, Christine L. Blackburn, Cordula Hopmann
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Abstract
This invention provides novel compounds derived from a marine sponge, Adocia sp., that specifically modulat kinesin activity by targeting the kinesin motor domain and mimicking the activity a microtubule. The compounds act as potent anti-mitogens are useful in a wide variety of in vitro and in vivo applications.
Claims78
A compound having a formula
- 6
- wherein R1 and R2 are either independent monovalent moieties independently selected from the group of H, hemiterpenes, terpene monomers and terpene oligomers such that at least one of R1 and R2 is not H,
- or R1 and R2 are combined to form a single divalent terpene moiety selected from the group consisting of hemiterpenes, terpene monomers and terpene oligomers;
- X1 and X2 are the same or different and are anionic derivatives of an organic group, an inorganic group or a group which is a combination of organic and inorganic groups;
- Y+n is an organic or inorganic cation;
- m is either 1 or 2;
- and
- n is either 1 or 2.
A composition for in vivo modulation of kinesin motor activity, said composition comprising:
- a pharmaceutically acceptable excipient;
- and
- a compound having the formula
- 11
- wherein R1 and R2 are either independent monovalent moieties independently selected from the group of H, hemiterpenes, terpene monomers and terpene oligomers such that at least one of R1 and R2 is not H,
- or R1 and R2 are combined to form a single divalent terpene moiety selected from the group consisting of hemiterpenes, terpene monomers and terpene oligomers;
- X1 and X2 are the same or different and are anionic derivatives of an organic group, an inorganic group or a group which is a combination of organic and inorganic groups;
- Y+n is an organic or inorganic cation;
- m is either 1 or 2;
- and
- n is either 1 or 2.
A method for modulating kinesin motor activity in a cell, said method comprising the step of:
- (i) contacting s aid cell with a compound having the formula
- 16
- wherein R1 and R2 are either independent monovalent moieties independently selected from the group of H, hemiterpenes, terpene monomers and terpene oligomers such that at least one of R1 and R2 is not H,
- or R1 and R2 are combined to form a single divalent terpene moiety selected from the group consisting of hemiterpenes, terpene monomers and terpene oligomers;
- X1 and X2 are the same or different and are anionic derivatives of an organic group, an inorganic group or a group which is a combination of organic and inorganic groups;
- Y+n is an organic or inorganic cation;
- m is either 1 or 2;
- and
- n is either 1 or 2.
A method of assaying a test compound for kinesin modulatory activity, said method comprising the steps of:
- (i) contacting a microtubule and a kinesin motor with said test compound having the formula
- 21
- wherein R1 and R2 are either independent monovalent moieties independently selected from the group of H, hemiterpenes, terpene monomers and terpene oligomers such that at least one of R1 and R2 is not H,
- or R1 and R2 are combined to form a single divalent terpene moiety selected from the group consisting of hemiterpenes, terpene monomers and terpene oligomers;
- X1 and X2 are the same or different and are anionic derivatives of an organic group, an inorganic group or a group which is a combination of organic and inorganic groups;
- Y+n is an organic or inorganic cation;
- m is either 1 or 2;
- and
- n is either 1 or 2;
- and
- (ii) detecting a change in kinesin motor activity resulting from said contacting.
A kit for modulating kinesin motor activity, said kit comprising a container containing compound having a formula
- 23
- wherein R1 and R2 are either independent monovalent moieties independently selected from the group of H, hemiterpenes, terpene monomers and terpene oligomers such that at least one of R1 and R2 is not H,
- or R1 and R2 are combined to form a single divalent terpene moiety selected from the group consisting of hemiterpenes, terpene monomers and terpene oligomers;
- X1 and X2 are the same or different and are anionic derivatives of an organic group, an inorganic group or a group which is a combination of organic and inorganic groups;
- Y+n is an organic or inorganic cation;
- m is either 1 or 2;
- and
- n is either 1 or 2.
A method of identifying a compound that specifically modulates a kinesin motor at a microtubule binding site, said method comprising the steps of:
- (i) assaying for competitive inhibition of said motor by said molecule at a kinesin ATPase site;
- (ii) assaying for competitive inhibition of said motor by said molecule at a microtubule binding site;
- (iii) identifying said small molecule as a kinesin modulator specific to a microtubule binding site when said small molecule is a competitive modulator at said microtubule binding site, but not at said ATPase site.
A method of modulating kinesin motor activity, said method comprising contacting said kinesin motor with a small organic molecule that competitively inhibits said kinesin motor at a microtubule binding site.
A method of modulating kinesin motor activity, said method comprising contacting said kinesin motor with a small organic molecule that competitively inhibits said kinesin motor at a microtubule binding site.
A method of identifying an agent that modulates the kinesin inhibitory activity of an Adocia kinesin inhibitor, said method comprising:
- (i) contacting a microtubule, a kinesin motor, and an Adocia kinesin inhibitor with a candidate agent;
- and
- (ii) detecting a change in the kinesin inhibitory activity of the Adocia kinesin inhibitor resulting from said contacting, wherein a change indicates the identification of an agent that modulates the kinesin inhibitory activity of the Adocia kinesin inhibitor.
A method of identifying an agent that interferes with the binding of an Adocia kinesin inhibitor with a kinesin, said method comprising:
- (i) contacting a kinesin and an Adocia kinesin inhibitor with a candidate agent;
- and
- (ii) detecting a decrease in the binding of the Adocia kinesin inhibitor with the kinesin resulting from said contacting, wherein a decrease indicates the identification of an agent that interferes with the binding of the Adocia kinesin inhibitor and the kinesin.
A complex comprising an Adocia kinesin inhibitor and a kinesin.
Dependencies are inferred from the claim text.