Use of EP4 receptor antagonists for the treatment of NASH-associated liver cancer
This invention is directed to prostaglandin E2 receptor 4 (EP4) antagonists useful in the treatment of nonalcoholic steatohepatitis (NASH)-associated liver cancer in a human or animal. The method comprises administering one or more of Compound A, Compound B or Compound C, or pharmaceutically acceptable salts thereof, as the EP4 antagonist(s). The method may include a pharmaceutical composition comprising the EP4 antagonist, and may include one or more other active agents and/or therapies.
1. A method for the treatment of NASH-associated liver cancer which comprises administering a pharmaceutically effective amount of an EP4 antagonist to a human or an animal in need thereof,
wherein the EP4 antagonist is at least one compound selected from the group consisting of:
4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]-benzoic acid (Compound A), and
4-((1S)-1-{[5-chloro-2-(4-fluorophenoxy)benzoyl]amino}ethyl)benzoic acid (Compound B),
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , further comprising administering the pharmaceutically effective amount of the EP4 antagonist in combination with a second active agent, an anti-tumor therapy or both.
3. The method of claim 2 , wherein the second active agent is an immune checkpoint inhibitor.
4. The method of claim 2 , wherein the second active agent is a PD-1 inhibitor.
5. The method of claim 1 , wherein the EP4 antagonist is 4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]-benzoic acid (Compound A), or a pharmaceutically acceptable salt thereof.
6. The method of claim 5 , further comprising administering the pharmaceutically effective amount of the EP4 antagonist in combination with a second active agent, an anti-tumor therapy or both.
7. The method of claim 6 , wherein the second active agent is an immune checkpoint inhibitor.
8. The method of claim 6 , wherein the second active agent is a PD-1 inhibitor.
9. A method of therapy for the treatment of NASH-associated liver cancer in a human or an animal in need thereof, which results in at least one effect selected from the group consisting of:
increasing DCs, mouse CD103 + DC or a corresponding DC class in the human or the animal, which activates anti-tumor immune function in the human or the animal,
decreasing Foxp3 + Treg cells which suppress anti-tumor immune function in the human or the animal,
increasing CD8 + /Treg population ratio in the human or the animal,
increasing population of activated CD8 + T cells in the human or the animal, and
decreasing PD-1 expression in CD8 + T cells in the human or the animal,
wherein the method comprises administering a therapeutically effective amount of an EP4 antagonist to the human or the animal,
wherein the EP4 antagonist is at least one compound selected from the group consisting of:
4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]-benzoic acid (Compound A), and
4-((1S)-1-{[5-chloro-2-(4-fluorophenoxy)benzoyl]amino}ethyl)benzoic acid (Compound B),
or a pharmaceutically acceptable salt thereof.
10. The method of claim 9 , further comprising administering the pharmaceutically effective amount of the EP4 antagonist in combination with a second active agent, an anti-tumor therapy or both.
11. The method of claim 10 , wherein the second active agent is an immune checkpoint inhibitor.
12. The method of claim 10 , wherein the second active agent is a PD-1 inhibitor.
13. The method of claim 9 , wherein the EP4 antagonist is 4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]-benzoic acid (Compound A), or a pharmaceutically acceptable salt thereof.
14. The method of claim 13 , further comprising administering the pharmaceutically effective amount of the EP4 antagonist in combination with a second active agent, an anti-tumor therapy or both.
15. The method of claim 14 , wherein the second active agent is an immune checkpoint inhibitor.
16. The method of claim 14 , wherein the second active agent is a PD-1 inhibitor.
17. The method of claim 1 , wherein the EP4 antagonist is 4-((1S)-1-{[5-chloro-2-(4-fluorophenoxy)benzoyl]amino}ethyl)benzoic acid (Compound B), or a pharmaceutically acceptable salt thereof.
18. The method of claim 17 , further comprising administering the pharmaceutically effective amount of the EP4 antagonist in combination with a second active agent, an anti-tumor therapy or both.
19. The method of claim 18 , wherein the second active agent is an immune checkpoint inhibitor.
20. The method of claim 18 , wherein the second active agent is a PD-1 inhibitor.
21. The method of claim 9 , wherein the EP4 antagonist is 4-((1S)-1-{[5-chloro-2-(4-fluorophenoxy)benzoyl]amino}ethyl)benzoic acid (Compound B), or a pharmaceutically acceptable salt thereof.
22. The method of claim 21 , further comprising administering the pharmaceutically effective amount of the EP4 antagonist in combination with a second active agent, an anti-tumor therapy or both.
23. The method of claim 22 , wherein the second active agent is an immune checkpoint inhibitor.
24. The method of claim 22 , wherein the second active agent is a PD-1 inhibitor.