Ras inhibitors
The disclosure features macrocyclic compounds, and pharmaceutical compositions and protein complexes thereof, capable of inhibiting Ras proteins, and their uses in the treatment of cancers.
1. A compound having the structure of Formula Ib:
or a pharmaceutically acceptable salt thereof,
wherein
A is optionally substituted thiazole;
Y is
wherein the carbonyl carbon is bonded to W;
W is
X 1 is CH (CH 3 );
X 4 is NH;
R 1 is optionally substituted pyridine;
R 2 is —CH 2 CH 3 ;
R 10 is hydrogen; and
R 12 and R 13 are —CH 3 .
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is
wherein ** indicates a bond to —CH(R 10 )—,
and R 1 is
3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein W is
and R 1 is
4. A pharmaceutical composition comprising a compound of claim 3 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
5. A method of treating cancer in a subject in need thereof, wherein the cancer comprises a Ras mutation, comprising administering to the subject a therapeutically effective amount of a compound of claim 3 , or a pharmaceutically acceptable salt thereof.
6. The method of claim 5 , wherein the Ras mutation is at position 12.
7. The method of claim 6 , wherein the Ras mutation is K-Ras G12D or K-Ras G12V.
8. The method of claim 5 , wherein the Ras mutation is at a position selected from the group consisting of G12C, G12D, G12V, G12R, G13C, G13D, and Q61K, or a combination thereof.
9. The method of claim 5 , wherein the cancer is pancreatic cancer.
10. The method of claim 5 , wherein the method further comprises administering an additional anticancer therapy.
11. The method of claim 10 , wherein the additional anticancer therapy is a K-Ras (OFF) inhibitor.
12. The method of claim 10 , wherein the additional anticancer therapy is a PD-L1 inhibitor or a PD-1 inhibitor.
13. The method of claim 10 , wherein the additional anticancer therapy is chemotherapy.
14. The method of claim 13 , wherein the chemotherapy comprises docetaxel.
15. A method of inhibiting a Ras protein in a cell, the method comprising contacting the cell with an effective amount of a compound of claim 3 , or a pharmaceutically acceptable salt thereof.
16. The method of claim 15 , wherein more than one Ras protein is inhibited in the cell.
17. The method of claim 15 , wherein the cell is a cancer cell.
18. The method of claim 17 , wherein the cancer cell is a pancreatic cancer cell.
19. The method of claim 15 , wherein the method further comprises administering an additional anticancer therapy.
20. The method of claim 19 , wherein the additional anticancer therapy is a K-Ras (OFF) inhibitor.
21. The method of claim 19 , wherein the additional anticancer therapy is a PD-L1 inhibitor or a PD-1 inhibitor.
22. The method of claim 19 , wherein the additional anticancer therapy is chemotherapy.
23. The method of claim 22 , wherein the chemotherapy comprises docetaxel.