PRMT5 inhibitors and uses thereof
View Patent ↗Described herein are methods of treating cancer using one or more PRMT5 inhibitors, for example using one or more compounds of Formulae (1-5) or (A-F), pharmaceutically acceptable salts thereof, and/or pharmaceutical compositions thereof. Described herein are methods of treating cancer using one or more PRMT5 inhibitors, for example using one or more compounds of Formulae (1-5) or (A-F), pharmaceutically acceptable salts thereof, and/or pharmaceutical compositions thereof.
1. A method of treating colon cancer, the method comprising administering a PRMT5 inhibitor to a subject having colon cancer, wherein the colon cancer is p53-positive.
2. The method of claim 1 , wherein tumor growth of the cancer is inhibited more than about 50%.
3. The method of claim 1 , wherein methyl mark of the cancer is reduced more than about 80%.
4. The method of claim 1 , wherein the PMRT5 inhibitor is a compound of Formula 2:
or a pharmaceutically acceptable salt thereof, wherein X is —C(R XC ) 2 —, —O—, —S—, or —NR XN —, wherein each instance of R XC is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R XN is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)R XA , or a nitrogen protecting group; R XA is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or,
wherein the PMRT5 inhibitor is a compound of Formula 3:
or a pharmaceutically acceptable salt thereof, wherein R XN is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)R XA , or a nitrogen protecting group; R XA is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or,
wherein the PMRT5 inhibitor is a compound of Formula 4:
Formula 4
or a pharmaceutically acceptable salt thereof, wherein X is —C(R XC ) 2 —, —O—, —S—, or —NR XN —, wherein each instance of R XC is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R XN is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)R XA , or a nitrogen protecting group; R XA is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or,
wherein the PMRT5 inhibitor is a compound of Formula 5:
or a pharmaceutically acceptable salt thereof, wherein each instance of a and b is independently 1 or 2, and X is —C(R XC ) 2 —, —O—, —S—, or —NR XN —, wherein each instance of R XC is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R XN is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)R XA , or a nitrogen protecting group; R XA is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
5. The method of claim 1 , wherein the PMRT5 inhibitor is a compound of Formula A:
or a pharmaceutically acceptable salt thereof.
6. The method of claim 1 , wherein the PMRT5 inhibitor is a compound of Formula B:
or a pharmaceutically acceptable salt thereof.
7. The method of claim 1 , wherein the PMRT5 inhibitor is a compound of Formula C:
or a pharmaceutically acceptable salt thereof.
8. The method of claim 1 , wherein the PMRT5 inhibitor is a compound of Formula E:
or a pharmaceutically acceptable salt thereof.
9. The method of claim 1 , wherein the PMRT5 inhibitor is a compound of Formula F:
or a pharmaceutically acceptable salt thereof.
10. The method of claim 1 further comprising diagnosing the subject as having colon cancer.
11. A method for treating colon cancer that is sensitive to treatment with a PRMT5 inhibitor, the method comprising administering to a subject a composition comprising a PRMT5 inhibitor wherein:
(a) the presence or absence of p53 has been detected in a biological sample obtained from the subject; and,
(b) the subject has been identified as having colon cancer that is sensitive to treatment with a PRMT5 inhibitor based upon the presence of p53 in the sample.
12. The method of claim 11 , wherein the PMRT5 inhibitor is a compound of Formula 2:
or a pharmaceutically acceptable salt thereof, wherein X is —C(R XC ) 2 —, —O—, —S—, or —NR XN —, wherein each instance of R XC is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R XN is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)R XA , or a nitrogen protecting group; R XA is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or,
wherein the PMRT5 inhibitor is a compound of Formula 3:
or a pharmaceutically acceptable salt thereof, wherein R XN is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)R XA , or a nitrogen protecting group; R XA is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or,
wherein the PMRT5 inhibitor is a compound of Formula 4:
or a pharmaceutically acceptable salt thereof, wherein X is —C(R XC ) 2 —, —O—, —S—, or —NR XN —, wherein each instance of R XC is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R XN is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)R XA , or a nitrogen protecting group; R XA is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or,
wherein the PMRT5 inhibitor is a compound of Formula 5:
or a pharmaceutically acceptable salt thereof, wherein each instance of a and b is independently 1 or 2, and X is —C(R XC ) 2 —, —O—, —S—, or —NR XN —, wherein each instance of R XC is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R XN is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)R XA , or a nitrogen protecting group; R XA is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
13. The method of claim 11 , wherein the PMRT5 inhibitor is a compound of Formula A:
or a pharmaceutically acceptable salt thereof.
14. The method of claim 11 , wherein the PMRT5 inhibitor is a compound of Formula B:
or a pharmaceutically acceptable salt thereof.
15. The method of claim 11 , wherein the PMRT5 inhibitor is a compound of Formula C:
or a pharmaceutically acceptable salt thereof.
16. The method of claim 11 , wherein the PMRT5 inhibitor is a compound of Formula E:
or a pharmaceutically acceptable salt thereof.
17. The method of claim 11 , wherein the PMRT5 inhibitor is a compound of Formula F:
or a pharmaceutically acceptable salt thereof.