Inhibitors of p97
One aspect of the invention relates to compounds that inhibit the activity of p97, such as by binding covalently to a cysteine residue in the active site. In certain embodiments, the invention relates to the treatment of disease, such as cancer, comprising administering a compound of the invention.
1. A method for treating cancer in a patient in need thereof, comprising inhibiting the activity of AAA p97 having the descriptive name, Valosin-containing protein, by contacting a cell with a therapeutically effective amount of a compound that binds to and inhibits p97, wherein the compound has a structure of formula (I):
wherein
R 1 is —C(O)—CH═CHR 6 or —C(O)—CH 2 —X, X is chloro, R 3 is H or —C(O)—CH═CH 2 , R 2 is hydrogen, R 4 is aryl, and R 5 is lower alkyl,
or pharmaceutically acceptable salts thereof.
2. The method of claim 1 , wherein the compound covalently binds to an active site of AAA p97 having the descriptive name Valosin-containing protein.
3. The method of claim 2 , wherein the compound forms a covalent bond with a cysteine residue of the active site.
4. The method of claim 3 , wherein the cysteine residue is Cys522.
5. The method according to claim 1 wherein R 1 has an atom susceptible to nucleophilic attack.