P62-ZZ chemical inhibitor
A method for treating a p62-mediated disease (e.g., multiple myeloma) in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one p62-ZZ inhibitor compound.
1. A method for treating multiple myeloma in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one p62-ZZ inhibitor compound of structural Formula I:
or a pharmaceutically acceptable salt or ester thereof, wherein:
Ar is an arylene or heteroarylene;
R 1 has a structure of:
wherein W is an alkanediyl; X is —NR 5 —, wherein R 5 is H; and Y is a hydroxyalkyl, an aminoalkyl, or a carboxylalkyl;
each R 2 is the same or different and has a structure of:
wherein Z is —NR 6 — or —O—; R 6 is H;
Z 1 is (—CH 2 —);
Cy is a 6-membered aryl ring; and
each R 4 is the same or different halogen; c is 1; a is 2; and
b is O.
2. The method of claim 1 , wherein a first R 2 group is in a meta position on the Ar ring of Formula I relative to the R 1 group, and a second R 2 group is in a para position on the Ar ring of Formula I relative to the R 1 group.
3. The method of claim 1 , wherein W is —CH 2 .
4. The method of claim 1 , wherein R 2 is
5. The method of claim 1 , wherein the p62-ZZ inhibitor is
wherein each R 7 , R 8 , and R 9 are the same or different and are selected from —F or —Cl; d is 0, e is 1, and f is 1.
6. The method of claim 1 , wherein the multiple myeloma is drug resistant multiple myeloma.
7. The method of claim 1 , further comprising co-administering at least one anti-cancer agent with the p62-ZZ inhibitor.
8. The method of claim 7 , further comprising inhibiting osteoclastogenesis and/or reducing osteoclast activation.
9. A method of inhibiting multiple myeloma cell growth, comprising contacting multiple myeloma cells with a compound, or a pharmaceutically acceptable salt or ester thereof, having a formula I of:
or a pharmaceutically acceptable salt or ester thereof, wherein:
Ar is an arylene or heteroarylene;
R 1 has a structure of:
wherein W is an alkanediyl; X is —NR 5 —, wherein R 5 is H; and
Y is a hydroxyalkyl, an aminoalkyl, or a carboxylalkyl;
each R 2 is the same or different and has a structure of:
wherein Z is —NR 6 — or —O—; R 6 is H;
Z 1 is (—CH 2 —);
Cy is a 6-membered aryl ring; and
each R 4 is the same or different halogen; c is 1; a is 2; and b is 0.
10. The method of claim 9 , wherein a first R 2 group is in a meta position on the Ar ring of Formula I relative to the R 1 group, and a second R 2 group ins in a para position on the Ar ring of Formula I relative to the R 1 group.
11. The method of claim 9 , wherein W is —CH 2 .
12. The method of claim 9 , wherein R 2 is
13. The method of claim 9 , wherein the p62-ZZ inhibitor is
wherein each R 7 , R 8 , and R 9 are the same or different and are selected from —F or —Cl; d is 0, e is 1, and f is 1.
14. The method of claim 1 , wherein W is —CH 2 , X is —NR 5 , and R is H.
15. The method of claim 1 , further comprising co-administering at least one anti-cancer agent with the p62-ZZ inhibitor.
16. The method of claim 15 , further comprising inhibiting osteoclastogenesis and/or reducing osteoclast activation.
17. The method of claim 9 , wherein W is —CH 2 , X is —NR 5 , and R is H.