Treatment for tumors driven by metabolic dysfunction
The present disclosure relates to modified or polymer conjugated MetAP2 inhibitors. The present disclosure also relates to methods of treating metabolically-driven diseases and disorders, such as certain cancers.
1. A method for treating, or ameliorating at least one symptom of, cancer in a subject in need thereof comprising administering at therapeutically effective amount of at least one polymer conjugate, wherein the polymer conjugate comprises the Formula
wherein, independently for each occurrence,
R 4 is H or C 1 -C 6 alkyl;
R 5 is H or C 1 -C 6 alkyl;
R 6 is C 2 -C 6 hydroxyalkyl;
Z is NH-AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 -C(O)-L or NH-AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 -C(O)-Q-X—Y—C(O)—W;
AA 1 is glycine, alanine, or H 2 N(CH 2 )mCO 2 H, wherein m is 2, 3, 4 or 5;
AA 2 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine;
AA 3 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine;
AA 4 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine;
AA 5 is a bond, or glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine;
AA 6 is a bond, or alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, or H 2 N(CH 2 ) m CO 2 H, wherein m is 2, 3, 4 or 5;
L is —OH, —O-succinimide, —O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, —NH 2 , —NH(C 2 -C 6 hydroxyalkyl), halide or perfluoroalkyloxy;
Q is NR, O, or S;
X is M-(C(R) 2 ) p -M-J-M-(C(R) 2 ) p -M-V;
M is a bond, or C(O);
J is a bond, or ((CH 2 ) q Q) r , C 5 -C 8 cycloalkyl, aryl, heteroaryl, NR, O, or S;
Y is NR, O, or S;
R is H or alkyl;
V is a bond or
R 9 is alkyl, aryl, aralkyl, or a bond; or R 9 taken together with Y forms a heterocyclic ring;
R 10 is amido or a bond;
R 11 is H or alkyl;
W is a Methionine aminopeptidase 2 (MetAP2) inhibitor moiety or alkyl;
x is in the range of 1 to about 450;
y is in the range of 1 to about 30;
n is in the range of 1 to about 100;
p is 0 to 20;
q is 2 or 3;
r is 1, 2, 3, 4, 5, or 6;
or a pharmaceutically acceptable salt, prodrug or analog thereof,
wherein the cancer is post-menopausal HR+/Her2− breast cancer, esophageal carcinoma, esophageal adenocarcinoma, cancer of the tongue, colorectal adenocarcinoma, gastro-intestinal stromal tumor (GIST), cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, gall bladder cancer, cholangiocarcinoma, liver cancer, clear-cell renal cancer, melanoma, multiple myeloma, thyroid cancer or combinations thereof,
wherein the subject has excessive visceral adiposity, elevated leptin levels, depressed adiponectin levels, a high leptin-to-adiponectin ratio, elevated fasting insulin levels, elevated fasting insulin levels accompanied by chronic inflammation, insulin resistance or any combination thereof, and
wherein the cancer is treated.
2. The method of claim 1 , wherein Z is represented by a formula selected from the group consisting of
3. The method of claim 1 , wherein the at least one polymer conjugate, or a pharmaceutically acceptable salt, prodrug or analog thereof, comprises the Formula
4. The method of claim 1 , wherein R 4 is methyl.
5. The method of claim 1 , wherein R 5 is methyl.
6. The method of claim 1 , wherein R 6 is 2-hydroxypropyl.
7. The method of claim 1 , wherein Z is —NH-AA 6 -C(O)-Q-X—Y—C(O)—W.
8. The method of claim 7 , wherein AA 6 is glycine.
9. The method of claim 1 , wherein Z is —NH-AA 5 -AA 6 -C(O)-Q-X—Y—C(O)—W.
10. The method of claim 9 , wherein AA 5 is leucine and AA 6 is glycine.
11. The method of claim 9 , wherein AA 5 is valine and AA 6 is glycine.
12. The method of claim 9 , wherein AA 5 is phenylalanine and AA 6 is glycine.
13. The method of claim 9 , wherein AA 5 is glycine and AA 6 is glycine.
14. The method of claim 1 , wherein Z is —NH-AA 3 -AA 4 -AA 5 -AA 6 -C(O)-Q-X—Y—C(O)—W.
15. The method of claim 14 , wherein AA 5 is leucine and each of AA 3 , AA 4 , or AA 6 is glycine.
16. The method of claim 14 , wherein AA 5 is valine and each of AA 3 , AA 4 , or AA 6 is glycine.
17. The method of claim 14 , wherein AA 5 is phenylalanine and each of AA 3 , AA 4 , or AA 6 is glycine.
18. The method of claim 14 , wherein AA 3 is glycine, AA 4 is phenylalanine, AA 5 is leucine and AA 6 is glycine.
19. The method of claim 14 , wherein each of AA 3 , AA 4 , AA 5 and AA 6 is glycine.
20. The method of claim 1 , wherein -Q-X-Y is
21. The method of claim 1 , wherein W is
22. The method of claim 1 , wherein the ratio of x toy is in the range of about 30:1 to about 3:1.
23. The method of claim 1 , wherein the ratio of x to y is about 11:1.
24. The method of claim 1 , wherein administration of the therapeutically effective amount of the at least one polymer conjugate increases adiponectin, decreases leptin, decreases fasting insulin, decreases the leptin-to-adiponectin ratio or combinations thereof in said subject.
25. The method of claim 1 , wherein said therapeutically effective amount is from about 0.0001 mg/kg of body weight per day to about 5 mg/kg of body weight per day.
26. The method of claim 1 , wherein said therapeutically effective amount is from or about 0.001 mg/kg of body weight per day to about 0.1 mg/kg of body weight per day.
27. The method of claim 1 , wherein said polymer conjugate is administered from about 1 to about 5 times per week.
28. The method of claim 1 , wherein said polymer conjugate is administered in a q4d dosing schedule.
29. The method of claim 1 , wherein said polymer conjugate is administered in a q7d dosing schedule.
30. The method of claim 1 , wherein said subject is treated for at least about six months.
31. The method of claim 1 , wherein said subject is treated for at least about one year.
32. The method of claim 1 , wherein said compound polymer conjugate is administered parenterally.
33. The method of claim 1 , wherein said polymer conjugate is administered subcutaneously.
34. The method of claim 1 , further comprising administering a second active agent.
35. The method of claim 1 , wherein said compound is provided as a pharmaceutical composition comprising said polymer conjugate and a pharmaceutically acceptable carrier.
36. The method of claim 1 , wherein said polymer conjugate is administered once every two weeks.
37. The method of claim 1 , wherein said subject is treated for at least about one month.
38. The method of claim 1 , wherein the cancer is hormone receptor-positive breast cancer.