Small molecule RPN13 inhibitors with antitumor properties
Compounds of formula (I), (II), and (III) having the structure shown below are presented: wherein R-R 6 are defined herein. These molecules work as proteasome inhibitors and bind to the RPN13 subunit of the 19S regulatory particle, and can be used in methods of treating a condition or a disease, such as cancer, in a mammal.
1 . A compound of formula (I):
wherein
R is H, C(O)CH 2 Cl, C(O)CH 3 , C(O)CH═CH 2 , or C(O)N(H) CH 3 ;
R 1 at each occurrence is independently selected from NO 2 , halogen, and
R 2 is a side group from an alpha amino acid;
R 3 is C 1 -C 6 alkyl, or phenyl, wherein C 1 -C 6 alkyl is a saturated, linear or branched carbon chain having up to 6 carbons;
and n at each occurrence is independently an integer from 0-5, inclusive;
or a pharmaceutically acceptable salt, hydrate, or solvate thereof;
wherein when R 2 is the benzyl side group from phenylalanine and R 3 is hydrogen, R is C (O)CH 2 Cl; and
wherein the compound of formula (I) is not
2 . The compound of claim 1 wherein R 3 is methyl.
3 . The compound of claim 1 , wherein R 2 is the (CH 2 ) 4 NH 2 side group from lysine or the benzyl side group from phenylalanine.
4 . The compound of claim 1 , wherein R 2 is the benzyl side group from phenylalanine; and R is C(O)CH 2 Cl.
5 . The compound of claim 4 , wherein each (R 1 ) n is 3,4-dichloro, 4-nitro, 2-fluoro or 4-fluoro.
6 . The compound of claim 5 , selected from the group consisting of
7 . The compound of claim 1 , wherein R 2 is the benzyl side group from phenylalanine; R is H or C(O)CH 2 Cl;
R is nitro or fluorine; and
R 3 is methyl.
8 . The compound of claim 7 , selected from the group consisting of:
9 . The compound of claim 1 , wherein, when R3-methyl, the configuration at Carbon 2 of formula (I) is the R configuration, S configuration, or equimolar mixture of R and S.
10 . The compound of claim 9 , wherein the configuration at Carbon 2 is the S configuration.
11 . A method of treating a condition or a disease in a mammal by administering to the mammal a therapeutically effective dose of a compound of claim 1 to the mammal.
12 . The method of claim 11 , wherein the compound is selected from the group consisting of:
13 . The method of claim 11 , wherein the condition or disease is a type of cancer.
14 . The method of claim 13 , wherein the cancer is selected from the group consisting of breast cancer, cervical cancer, ovarian cancer, multiple myeloma, breast cancer, pancreatic cancer, and a cancer associated with Human Papilloma Virus (HPV).
15 . The method of claim 13 , wherein the cancer is ovarian cancer.
16 . The method of claim 11 , wherein the compound is administered in combination with at least one other therapeutic agent.
17 . The method of claim 16 , wherein the at least one other therapeutic agent is a proteasome inhibitor or a DNA damaging agent, bortezomib or cisplatin.
18 . The compound of claim 1 , wherein
R is H, or C(O)CH 2 Cl;
R 1 is NO 2 or halogen;
n is 1 or 2;
R 2 is benzyl; and
R 3 is methyl.