Thailanstatin analogs
The invention provides novel cytotoxic compounds and cytotoxic conjugates comprising these cytotoxic compounds and cell-binding agents. More specifically, this invention relates to novel thailanstatin A analogs, useful as cytotoxic small molecule toxins in antibody-drug conjugates (ADCs). The present invention further relates to compositions including these cytotoxic compounds and ADCs, and methods for using these toxins and ADCs to treat pathological conditions including cancer.
1. A compound of Formula (III):
T-L′-Ab (III)
or a pharmaceutically acceptable salt thereof, wherein:
L′ is a linker moiety;
T is a radical of Formula (I′):
wherein:
R is selected from the group consisting of: —(CH 2 ) n —R 1 ; -5 to 6 membered heteroaryl, where heteroaryl is optionally substituted with one or more of halogen, —CF 3 , —C 1-6 alkyl, and —O—C 1-6 alkyl;
—C(R 2 )=N—R 3 ; —CH(CF 3 )NH(CH 2 ) m CH 3 ; —C(R a R b )NH(CH 2 ) m CH 3 ;
—C(halogen)═CH(CH 2 ) m CH 3 ; —SO 2 —NH(CH 2 ) m CH 3 ; —O(CO)-aryl; —O(CO)— heteroaryl; —NR a R b ; and —NH-heteroaryl;
wherein R 1 is —O—CR a R b (CH 2 ) m CH 3 or —N—CR a R b (CH 2 ) m CH 3 ;
wherein R a and R b , together with the atoms to which they are joined, form a C 3-10 heterocyclyl ring;
R 2 is —CN or —NH(CH 2 ) m CH 3 ;
R 3 is —(CH 2 ) m CH 3 or —O—(CH 2 ) m CH 3 ;
each n is independently 1, 2, or 3;
each m is independently 0, 1, 2, or 3; and
Ab is an antibody.
2. The compound or salt according to claim 1 , wherein R is selected from the group consisting of:
3. The compound according to claim 1 , wherein L′ is selected from the group consisting of Formula (B 1 ), Formula (B 2 ), Formula (B 3 ), and Formula (B 4 ):
wherein q is 3, 4, 5, 6, 7, 8, 9, or 10.
4. The compound or salt according to claim 1 , wherein the compound of Formula (III) is selected from the group consisting of:
wherein q is 3, 4, 5, 6, 7, 8, 9, or 10; and n is 1, 2, 3, or 4.
5. The compound according to claim 1 , having structure 11 :
wherein tras is trastuzumab.
6. The compound or salt according to claim 1 , wherein the antibody is selected from the group consisting of trastuzumab, pertuzumab, gemtuzumab, and vadastuximab.
7. The compound or salt according to claim 1 , wherein the antibody binds to one or more tumor-associated antigens or cell-surface receptors.
8. The compound or salt according to claim 1 , wherein the antibody binds to a tumor-associated antigen selected from the group consisting of HER2, CD33, CD70, MUC1/CanAg, MUC16, CD151 and ITGaV.
9. A pharmaceutical composition comprising a therapeutically effective amount of the compound or salt of claim 1 and a pharmaceutically acceptable diluent, carrier or excipient.
10. The method for the treatment of cancer comprising administering to a patient a therapeutically effective amount of the pharmaceutical composition of claim 9 , wherein the cancer is selected from carcinomas of the bladder, breast, cervix, colon, endometrium, kidney, lung, esophagus, ovary, prostate, pancreas, skin, stomach and testes, leukemias and lymphomas.
11. A compound of Formula (III):
T-L′-Ab (III)
or a pharmaceutically acceptable salt thereof, wherein:
L′ is a linker moiety;
T is a radical of Formula (I′):
wherein:
R is selected from the group consisting of:
and
Ab is an antibody.
12. The method of claim 10 wherein the cancer is HER2-expressing breast cancer.
13. The compound of claim 1 of Formula (III):
T-L′-Ab (III)
or a pharmaceutically acceptable salt thereof, wherein:
L′ is a linker moiety;
T is a radical of Formula (I′):
wherein:
R is selected from the group consisting of:
14. The compound of claim 13 wherein R is:
15. The compound of claim 13 wherein R is:
16. The compound of claim 13 wherein R is:
17. The compound of claim 13 wherein Ab is trastuzumab.