Combination Therapies Using PRMT5 Inhibitors for the Treatment of Cancer
This disclosure relates to methods of treating cancer. This disclosure further relates to treating cancer in a subject with compounds that are inhibitors of PRMT5, particularly in combination with KRAS G12C inhibitors.
1 . A method for treating cancer in a subject, the method comprising:
administering to the subject a therapeutically effective amount of a Kirsten rat sarcoma viral oncogene homolog glycine-to-cysteine (KRAS G12C ) inhibitor and a therapeutically effective amount of a protein arginine N-methyl transferase 5 (PRMT5) inhibitor.
2 . The method of claim 1 , wherein the cancer comprises methylthioadenosine phosphorylase (MTAP) gene homozygous deletion.
3 . The method of claim 1 , wherein the cancer comprises KRAS G12C gene mutation.
4 . The method of claim 2 , wherein the cancer further comprise a cyclin-dependent kinase inhibitor 2A (CDKN2A) gene homozygous deletion.
5 . The method of claim 1 , wherein the cancer is lung cancer, pancreatic cancer, colon cancer, head and neck cancer, esophageal cancer, or melanoma.
6 . The method of claim 1 , wherein the cancer is lung cancer, such as non-small cell lung cancer (NSCLC).
7 . The method of claim 1 , wherein the cancer is pancreatic or colon cancer.
8 . The method of claim 1 , wherein the KRAS G12C inhibitor is selected from adagrasib, sotorasib, JNJ-74699157, GDC-6036, LY3499446, JDQ443, D-1553, and combinations thereof.
9 . The method of claim 1 , wherein the KRAS G12C inhibitor is adagrasib.
10 . The method of claim 1 , wherein the KRAS G12C inhibitor is sotorasib.
11 . The method of claim 1 , wherein the PRMT5 inhibitor is a methylthioadenosine (MTA)-cooperative PRMT5 inhibitor.
12 . The method of claim 1 , wherein the PRMT5 inhibitor is a compound of Formula IIA, IIB or IIC:
or a pharmaceutically acceptable salt thereof, wherein:
A is CR 9 or N;
D is (C(R 9 ) 2 ) 1-2 —NH 2 ,
or D is
where the methylene is bonded to E where E is C;
E is C, CR 9 or N;
each L is independently a bond or C 1-C3 alkylene;
W is CR 9 or N;
each X is independently a bond, O, S, —NR 4 — or —NR 4 C(O)—;
each Z is independently a bond, —SO—, —SO 2 —, —CH(OH)— or —C(O)—;
each R 2 is independently hydroxy, halogen, cyano, cyanomethyl, —(NR 4 ) 2 , hydroxyalkyl, alkoxy, —SO 2 C 1 -C 3 alkyl, —X-arC 1 -C 3 alkyl, heteroalkyl, C 2 -C 4 alkynyl, —X-haloalkyl, —X-C 1 -C 5 alkyl, —Z-C 1 -C 5 alkyl, heterocyclyl, —X-L-cycloalkyl, —Z-cycloalkyl, —X-aryl, —Z-aryl, or —X-heteroaryl, wherein the heterocyclyl, the cycloalkyl, the aryl and the heteroaryl are optionally substituted with one or more R 5 ;
each R 4 is independently hydrogen or C 1 -C 3 alkyl;
each R 5 is independently cyano, oxo, halogen, C 1 -C 3 alkyl, hydroxyalkyl, hydroxy, alkoxy, alkoxy-C 1 -C 3 alkyl, —X-haloalkyl, —Z-cycloalkyl, —X-arC 1 -C 3 alkyl, —X-arC 1 -C 3 alkyl substituted with cyano, —X-L-cycloalkyl optionally substituted with C 1 -C 3 alkyl or oxo, —X-L-heteroaryl optionally substituted with one or more C 1 -C 3 alkyl or oxo, —X-L-heterocyclyl optionally substituted with one or more C 1 -C 3 alkyl or oxo, or —X-aryl;
R 6 is hydrogen, halogen, C 1 -C 3 alkyl, haloalkyl, hydroxy, alkoxy, C 1 -C 3 alkyl-alkoxy, N(R 9 ) 2 , NR 9 C(O)R 9 , C(O)R 9 , oxetane and THF;
R 7 is H or C 1 -C 3 alkyl optionally substituted with one or more halogen;
R 8 is H or C 1 -C 3 alkyl; and
each R 9 is independently H or C 1 -C 3 alkyl, halogen or haloalkyl.
13 . The method of claim 1 , wherein the PRMT5 inhibitor is a compound of Formula IIIA:
or a pharmaceutically acceptable salt thereof, wherein
A is CR 9 or N;
D is —CH 2 −NH 2 ,
W is CR 9 or N, where R 9 is H or C 1 -C 3 alkyl;
R 2 is
where R 56 is hydrogen, fluoro, chloro, or methyl,
G, Q, J and U are independently selected from C(H), C(R 5 ), and N, provided only one or two of G, Q, J, and U can be N;
each R 5 is independently hydroxy, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 6 cycloalkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, or C 1 -C 3 alkoxyC 1 -C 3 alkyl;
R 6 is hydrogen, halogen, C 1 -C 6 alkyl, hydroxy, C 1 -C 6 alkoxy, C 1 -C 3 alkoxyC 1 -C 3 alkyl, C 3 -C 6 heterocycloalkyl, —C(O)-C 1 -C 3 haloalkyl, or —NR 15 (CO)R 16 , where R 15 is hydrogen or methyl, and R 16 is C 1 -C 3 alkyl; and
R 7 is C 1 -C 3 alkyl or C 1 -C 3 haloalkyl.
14 . The method of claim 13 , wherein the PRMT5 inhibitor is:
or a pharmaceutically acceptable salt thereof.
15 . The method of claim 1 , wherein the PRMT5 inhibitor is a compound of Formula IIIB:
or a pharmaceutically acceptable salt thereof, wherein
A is CR 9 or N;
D is —CH 2 —NH 2 ,
W is CR 9 or N, where R 9 is H or C 1 -C 3 alkyl;
R 51 is hydrogen, fluoro, chloro, or methyl, or R 51 and R 52 together with atoms to which they are attached form a C 4 -C 6 heterocycloalkyl (e.g, hydrofuranyl);
R 52 is fluoro, chloro, or methyl, or R 52 and R 53 together with atoms to which they are attached form a phenyl;
R 53 is hydrogen, fluoro, chloro, or methyl;
R 54 is hydrogen, halogen, C 1 -C 3 alkyl, or C 1 -C 3 alkoxy;
L 5 is —O— or —CH 2 —;
R 6 is hydrogen, halogen, C 1 -C 6 alkyl, hydroxy, C 1 -C 6 alkoxy, C 1 -C 3 alkoxyC 1 -C 3 alkyl, C 3 -C 6 heterocycloalkyl, —C(O)-C 1 -C 3 haloalkyl, or —NR 15 (CO)R 16 , where R 15 is hydrogen or methyl, and R 16 is C 1 -C 3 alkyl;
R 7 is C 1 -C 3 alkyl or C 1 -C 3 haloalkyl.
16 . The method of claim 15 , wherein:
A is —CH or —CCH 3 ;
D is —CH 2 —NH 2 ;
W is —CH, —CCH 3 , or N;
R 51 , R 52 , R 53 , and R 54 are each independently selected from hydrogen, fluoro, chloro, or methyl;
L 5 is —O—;
R 6 is hydrogen, fluoro, chloro, or methyl; and
R 7 is C 1 -C 2 alkyl or C 1 -C 2 haloalkyl.
17 . The method of claim 15 , wherein:
A and W are —CH;
D is —CH 2 —NH 2 ;
R 51 , R 52 , and R 53 are each independently selected from hydrogen, fluoro, chloro, and methyl;
R 54 is hydrogen;
L 5 is —O—;
R 6 is hydrogen; and
R 7 is methyl.
18 . The method of claim 15 , wherein:
A and W are —CH;
D is —CH 2 —NH 2 ;
R 51 and R 52 are each independently selected from fluoro, chloro, and methyl;
R 53 and R 54 are hydrogen;
L 5 is —O—;
R 6 is hydrogen; and
R 7 is methyl.
19 . The method of claim 15 , wherein the PRMT5 inhibitor is:
or a pharmaceutically acceptable salt thereof.
20 . The method of claim 15 , wherein the PRMT5 inhibitor is:
(MRTX1719) or a pharmaceutically acceptable salt thereof.
21 . The method of claim 1 , wherein the PRMT5 inhibitor is MRTX1719 or a pharmaceutically acceptable salt thereof, and the KRAS G12C inhibitor is adagrasib.
22 . The method of claim 1 , wherein the PRMT5 inhibitor is MRTX1719 or a pharmaceutically acceptable salt thereof, and the KRAS G12C inhibitor is sotorasib.
23 . The method of claim 1 , wherein the PRMT5 inhibitor is a compound of Formula IIIC:
or a pharmaceutically acceptable salt thereof, wherein
A is CR 9 or N;
D is —CH 2 —NH 2 ,
W is CR 9 or N, where R 9 is H or C 1 -C 3 alkyl;
G, Q, J and U are independently selected from C(H), C(R 5 ), and N, provided only one or two of G, Q, J, and U can be N;
each R 5 is independently hydroxy, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 6 cycloalkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, or C 1 -C 3 alkoxyC 1 -C 3 alkyl;
R 6 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, hydroxy, C 1 -C 6 alkoxy, C 1 -C 3 alkoxyC 1 -C 3 alkyl, C 3 -C 6 heterocycloalkyl, —C(O)-C 1 -C 3 haloalkyl, —N(R 9 ) 2 , or —NR 15 (CO)R 16 ,
where each R 9 is independently H or C 1 -C 3 alkyl, R 15 is hydrogen or methyl, and R 16 is C 1 -C 3 alkyl; and
R 7 is C 1 -C 3 alkyl or C 1 -C 3 haloalkyl.
24 . The method of claim 23 , wherein the PRMT5 inhibitor is:
or a pharmaceutically acceptable salt thereof.
25 . The method of claim 1 , wherein the therapeutically effective amount of the PRMT5 inhibitor is in the range of about 0.01 to 300 mg/kg per day.
26 . The method of claim 1 , wherein the therapeutically effective amount of the PRMT5 inhibitor is in the range of about 0.1 to 100 mg/kg per day.
27 . The method of claim 1 , wherein the therapeutically effective amount of the PRMT5 inhibitor is less than 1% of, e.g., less than 10%, or less than 25%, or less than 50% of the clinically-established therapeutic amount.
28 . The method of claim 1 , wherein the therapeutically effective amount of the KRAS G12C inhibitor is in the range of about 0.01 to 300 mg/kg per day.
29 . The method of claim 1 , wherein the therapeutically effective amount of the KRAS G12C inhibitor is in the range of about 0.1 to 100 mg/kg per day.
30 . The method of claim 1 , wherein the therapeutically effective amount of the KRAS G12C inhibitor is less than 1% of, e.g., less than 10%, or less than 25%, or less than 50% of the clinically-established therapeutic amount.
31 . The method of claim 1 , wherein the KRAS G12C inhibitor and the PRMT5 inhibitor are administered sequentially.
32 . The method of claim 1 , wherein the KRAS G12C inhibitor and the PRMT5 inhibitor are administered simultaneously.
33 . The method of claim 1 , wherein the subject previously received or completed a first-line chemotherapy.
34 . The method of claim 33 , wherein the first-line chemotherapy is platinum-and/or taxane-based chemotherapy.