MK2 inhibitors and uses thereof
The present invention provides compounds, compositions thereof, and methods of using the same.
1. A method for inhibiting activity of MK2 kinase, or a mutant thereof, in a biological sample comprising the step of contacting said biological sample with a compound of formula XX:
or a pharmaceutically acceptable salt thereof, wherein:
T is —NH— or —O—;
R is hydrogen or an optionally substituted C 1-6 aliphatic;
R 1 is methyl;
R 2 is halogen, —CN, —SR y , —S(O)R y , —SO 2 R y , —OSO 2 R y , —OC(O)R y , or —OP(O) 2 OR y ; and
R y is selected from optionally substituted C 1-6 aliphatic or optionally substituted phenyl.
2. The method according to claim 1 , wherein -T- is —O—.
3. The method according to claim 1 , wherein R 2 is chloro.
4. The method according to claim 1 , wherein R is C 1-6 aliphatic substituted with oxo, halogen, —CN, —(CH 2 ) 0-4 R ∘ , —(CH 2 ) 0-4 OR ∘ , or —(CH 2 ) 0-4 S(O) 2 R ∘ , wherein R ∘ is C 1-6 aliphatic.
5. The method according to claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
6. The method according to claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
7. The method according to claim 1 , wherein the MK2 kinase, or a mutant thereof, activity is inhibited irreversibly.
8. The method according to claim 7 , wherein the MK2 kinase, or a mutant thereof, activity is inhibited irreversibly by covalently modifying Cys140 of MK2.
9. A method for inhibiting activity of MK2 kinase, or a mutant thereof, in vitro comprising the step of contacting MK2 kinase, or mutant thereof, with a compound of formula XX:
or a pharmaceutically acceptable salt thereof, wherein:
T is —NH— or —O—;
R is hydrogen or an optionally substituted C 1-6 aliphatic;
R 1 is methyl;
R 2 is halogen, —CN, —SR y , —S(O)R y , —SO 2 R y , —OSO 2 R y , —OC(O)R y , or —OP(O) 2 OR y ; and
R y is selected from optionally substituted C 1-6 aliphatic or optionally substituted phenyl.
10. The method according to claim 9 , wherein -T- is —O—.
11. The method according to claim 8 , wherein R 2 is chloro.
12. The method according to claim 9 , wherein R is C 1-6 aliphatic substituted with oxo, halogen, —CN, —(CH 2 ) 0-4 R ∘ , —(CH 2 ) 0-4 OR ∘ , or —(CH 2 ) 0-4 S(O) 2 R ∘ , wherein R ∘ is C 1-6 aliphatic.
13. The method according to claim 9 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
14. The method according to claim 9 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
15. The method according to claim 9 , wherein the MK2 kinase, or a mutant thereof, activity is inhibited irreversibly.
16. The method according to claim 15 , wherein the MK2 kinase, or a mutant thereof, activity is inhibited irreversibly by covalently modifying Cys140 of MK2.
17. The method according to claim 1 , wherein the biological sample is a culture or extract thereof.
18. The method according to claim 1 , wherein inhibiting activity of MK2 kinase, or a mutant thereof, is within a biological assay.
19. The method according to claim 17 , wherein inhibiting activity of MK2 kinase, or a mutant thereof, is within a biological assay.
20. The method according to claim 9 , wherein inhibiting activity of MK2 kinase, or a mutant thereof, is within a biological assay.