Therapeutic compositions and methods
PAD4 inhibitory compositions and methods for their use in treatment of cancer and autoimmune disease are provided according to embodiments of the present invention.
1. A method of inhibiting peptidylarginine deiminase 4 (PAD4) activity in a subject, comprising:
administering a therapeutically effective amount of a composition comprising a compound having the structural formula selected from the group consisting of:
where n is 1 or 2; X is halogen; each Y is independently H, halogen, an O-linked aliphatic substituent or an N-linked aliphatic substituent; R 1 is an aromatic substituent; and R 2 is an aliphatic or aromatic substituent;
a salt, stereoisomer, hydrate, amide or ester thereof; and a mixture of any two or more thereof.
2. The method of claim 1 , wherein the composition comprises a compound selected from the group consisting of: YW3-56F, YW3-56Br, YW-56A, YW3-56A-F, YW3-56A-Br.
3. The method of claim 1 , wherein the composition comprises a compound having the structural formula:
where n is 1 or 2; X is halogen; Y 1 and Y 2 are each independently H, halogen, an O-linked aliphatic substituent or an N-linked aliphatic substituent; R 1 is an aromatic substituent; and R 2 is an aliphatic or aromatic substituent.
4. The method of claim 3 , wherein n is 1, Y 1 and Y 2 are both H and X is F or Cl.
5. The method of claim 4 , wherein the compound is selected from the group consisting of:
YW3-56, YW3-56F, YW3-56Br, YW3-56A, YW3-56A-F, YW3-56A-Br; a salt, stereoisomer, hydrate, amide or ester thereof; and a mixture of any two or more thereof.
6. The method of claim 1 wherein the subject is human.
7. The method of claim 1 wherein the subject has or is at risk of having cancer.
8. The method of claim 7 wherein the cancer is characterized by decreased levels or activity of one or more tumor suppressors.
9. The method of claim 8 wherein the tumor suppressor is p53.
10. The method of claim 1 , wherein administering the therapeutically effective amount of the composition to a subject detectably increases autophagy and/or decreases proliferation of cells of the cancer.
11. The method of claim 1 , further comprising administration of an additional therapeutic agent, an adjunct anti-cancer treatment or both an additional therapeutic agent and an adjunct anti-cancer treatment.
12. The method of claim 11 , wherein the additional therapeutic agent comprises administration of a histone deacetylase inhibitor.
13. The method of claim 12 , wherein the histone deacetylase inhibitor is SAHA.
14. The method of claim 1 wherein the subject has or is at risk of having an autoimmune disease.