PI4-kinase inhibitors and methods of using the same
Compounds and methods are provided for inhibiting a PI4-kinase. Methods of treating a pathogen infection and methods of treating cancer are also provided. The PI4-kinase inhibitor can be a compound that is a 5-aryl or heteroaryl-thiazole, e.g., as described herein. In certain embodiments, the PI4-kinase inhibitor is a substituted 2-amino-5-phenylthiazole or substituted 2-amino-5-pyridylthiazole compound. In some embodiments, the compounds have broad spectrum anti-infective activity against a variety of infective diseases, where the diseases are caused by pathogens containing a basic amino acid PIP-2 pincer (BAAPP) domain that interacts with phosphatidylinositol 4,5-bisphosphate (PIP-2) to mediate pathogen replication. Also provided are methods of treating a subject for cancer using a PI4-kinase inhibitor. Aspects of the methods include inhibiting PI4-kinase in a cancer cell to reduce cellular proliferation.
1. A compound of formula (I):
wherein:
Y 1 is selected from CH or N;
Y 2 is selected from S, O or NR 19 , wherein R 19 is selected from hydrogen, alkyl, and substituted alkyl;
R 1 is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
R 2 is selected from alkoxy and substituted alkoxy;
R 3 is selected from hydrogen, lower alkyl and substituted lower alkyl;
R 4 and R 5 are both methyl; and
R 6 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein the R 1 is selected from B2-B9:
wherein:
Y 3 and Y 5 are each independently selected from N and CR 11 , wherein R 11 is selected from hydrogen, R 10 , acyl, substituted acyl, carboxy, carboxyamide, substituted carboxyamide, sulfonyl, substituted sulfonyl, sulfonamide and substituted sulfonamide;
Y 6 is selected from CR 11 2 and NR 11 ;
each R 10 is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl and halogen;
n is an integer from 0 to 5;
m is an integer from 0 to 3;
p is an integer from 0 to 4; and
r is an integer from 0 to 2.
3. The compound of claim 1 , wherein the R 6 is selected from:
wherein:
Y 3 is selected from N and CR 11 , wherein R 11 is selected from hydrogen, R 10 , acyl, substituted acyl, carboxy, carboxyamide, substituted carboxyamide, sulfonyl, substituted sulfonyl, sulfonamide and substituted sulfonamide;
R 10 is one or more optional substituents independently selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl and halogen;
n is an integer from 0 to 5;
m is an integer from 0 to 3; and
p is an integer from 0 to 4.
4. The compound of claim 1 , wherein the compound is of one of the following formulae:
wherein
R 10 is one or more optional substituents independently selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, trifluoromethyl and halogen;
n is an integer from 0 to 5; and
R 12 , R 13 , and R 14 are each independently selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, and halogen.
5. The compound of claim 1 , wherein Y 2 is S.
6. The compound of claim 1 , wherein R 1 is selected from aryl, di-substituted aryl, tri-substituted aryl, tetra-substituted aryl, penta-substituted aryl, heteroaryl, and substituted heteroaryl.
7. The compound of claim 1 , wherein the compound is selected from
or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition comprising:
a compound of claim 1 ; and
a pharmaceutically acceptable excipient.
9. A method of inhibiting a PI4-kinase, the method comprising contacting a sample comprising the PI4-kinase with a compound of claim 1 .
10. The method of claim 9 , wherein the PI4-kinase is a PI4-Ill kinase.
11. A method of treating a subject for an infective disease condition, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the infective disease condition is caused by infection of a pathogen susceptible to PI4-kinase inhibition.
12. A method of treating a cancer susceptible to PI4-kinase inhibition, the method comprising:
administering to a subject with cancer a therapeutically effective amount of a compound of claim 1 .
13. The method of claim 12 , further comprising:
measuring the expression level or activity level of PI4KIIIβ in cancer cells of a biological sample obtained from the subject; and
determining whether the expression level or activity level of PI4KIIIβ in the cancer cells is elevated relative to one or more control cells.
14. The method of claim 12 , further comprising co-administering an effective amount of an additional agent to the subject.
15. A method of inhibiting proliferation of a cancer cell susceptible to PI4-kinase inhibition, the method comprising:
contacting a cancer cell with an effective amount of a compound of claim 1 .
16. An anti-cancer kit, comprising:
an effective dose of a compound of claim 1 ;
an effective dose of an additional anticancer agent; and
instructions for use in treating cancer.
17. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
18. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
19. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
20. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
21. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.