Splicing modulator antibody-drug conjugates and methods of use
Linker-drug compounds and antibody-drug conjugates that bind to human oncology targets are disclosed. The linker-drug compounds and antibody-drug conjugates comprise a splicing modulator drug moiety. The disclosure further relates to methods and compositions for use in the treatment of neoplastic disorders by administering the antibody-drug conjugates provided herein. In an embodiment, the splicing modulator comprises a pladienolide or a pladienolide derivative.
1. A compound of Formula (VIII):
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is chosen from hydrogen, C 1 -C 6 alkyl groups, C 1 -C 6 alkylalkoxy groups, C 1 -C 6 alkylamino groups, C 1 -C 6 alkylcarboxylic acid groups, C 1 -C 6 alkylhydroxy groups, C 3 -C 8 cycloalkyl groups, benzyl groups, C 3 -C 8 heterocyclyl groups, —O—C(═O)—(C 1 -C 6 alkyl) groups, and -CD 3 ;
R 3 is chosen from hydrogen, C 1 -C 6 alkyl groups, C 1 -C 6 alkylalkoxy groups, C 1 -C 6 alkylamino groups, C 1 -C 6 alkylcarboxylic acid groups, C 1 -C 6 alkylhydroxy groups, C 3 -C 8 cycloalkyl groups, benzyl groups, C 3 -C 8 heterocyclyl groups, and —O—C(═O)—(C 1 -C 6 alkyl) groups;
R 4 is chosen from hydrogen, hydroxyl groups, —O—(C 1 -C 6 alkyl) groups, —O—C(═O)—(C 1 -C 6 alkyl) groups, and C 1 -C 6 alkyl groups; and
R 10 is chosen from 3 to 10 membered carbocycles and 3 to 10 membered heterocycles, each of which is substituted with 0 to 3 R a ,
wherein each R 8 is independently chosen from halogens, C 1 -C 6 alkyl groups, —O—(C 1 -C 6 )alkyl groups, C 1 -C 6 alkylalkoxy groups, C 1 -C 6 alkylhydroxy groups,
S(═O) w -(4 to 7 membered heterocycles) wherein w is 1 or 2, 4 to 7 membered carbocycles, hydroxyl groups, -NR 15 R 16 , C 3 -C 8 cycloalkyl groups, benzyl groups, and C 3 -C 8 heterocyclyl groups,
wherein each R a is independently substituted with 0 to 3 groups independently chosen from halogens, hydroxyl groups, -NR 15 R 16 , C 1 -C 6 alkyl groups, —(C═O)—(C 1 -C 6 alkyl) groups, -(C═O)—(C 1 -C 6 alkyl)-(C 3 -C 10 heterocyclyl) groups, —S(═O) w -(C 3 -C 8 heterocyclyl) groups wherein w is 0, 1, or 2, and C 1 -C 6 alkylcarboxylic acid groups; and
R 15 and R 16 are each independently chosen from hydrogen, R 17 , —C(═O)-R 17 , and —C(═O)—O-R 17 , wherein R 17 is chosen from hydrogen, C 1 -C 6 alkyl groups, C 3 -C 8 cycloalkyl groups, benzyl groups, and C 3 -C 8 heterocyclyl groups;
wherein R 1 , R 3 , R 4 , R 15 , R 16 , and R 17 are each independently substituted with 0 to 3 groups independently chosen from halogens, hydroxyl groups, C 1 -C 6 alkyl groups, —O—(C 1 -C 6 alkyl) groups, -NR 15 R 16 , C 3 -C 8 cycloalkyl groups, C 1 -C 6 alkylhydroxy groups, C 1 -C 6 alkylalkoxy groups, benzyl groups, and C 3 -C 8 heterocyclyl groups.
2. The compound of claim 1 , wherein the compound is chosen from a compound of formula
and pharmaceutically acceptable salts thereof.
3. The compound of claim 1 , wherein the compound is chosen from a compound of formula
and pharmaceutically acceptable salts thereof.
4. The compound of claim 1 , wherein the compound is chosen from a compound of formula
and pharmaceutically acceptable salts thereof.
5. The compound of claim 1 , wherein the compound is chosen from a compound of formula
and pharmaceutically acceptable salts thereof.
6. The compound of claim 1 , wherein the compound is chosen from a compound of formula
and pharmaceutically acceptable salts thereof.
7. The compound of claim 1 , wherein the compound is chosen from a compound of formula
and pharmaceutically acceptable salts thereof.
8. The compound of claim 1 , wherein the compound is chosen from a compound of formula
and pharmaceutically acceptable salts thereof.
9. The compound of claim 1 , wherein the compound is chosen from a compound of formula
and pharmaceutically acceptable salts thereof.
10. The compound of claim 1 , wherein the compound is chosen from a compound of formula
and pharmaceutically acceptable salts thereof.
11. The compound of claim 1 , wherein the compound is chosen from a compound of formula
and pharmaceutically acceptable salts thereof.
12. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
13. A method of treating a subject having or suspected of having a neoplastic disorder, comprising administering to the subject a therapeutically effective amount of the compound of claim 1 .
14. The method of claim 13 , wherein the neoplastic disorder is a leukemia, a lymphoma, or a myeloma.
15. The method of claim 14 , wherein the myeloma is multiple myeloma.
16. A method of reducing or inhibiting growth of a tumor in a subject having or suspected of having a neoplastic disorder, comprising administering to the subject a therapeutically effective amount of the compound of claim 1 .
17. A compound of Formula (VIII-A):
or a pharmaceutically acceptable salt thereof,
wherein
R 1 is absent or is chosen from hydrogen, C 1 -C 6 alkyl groups, C 1 -C 6 alkylalkoxy groups, C 1 -C 6 alkylamino groups, C 1 -C 6 alkylcarboxylic acid groups, C 1 -C 6 alkylhydroxy groups, C 3 -C 8 cycloalkyl groups, benzyl groups, C 3 -C 8 heterocyclyl groups, —O—C(═O)—(C 1 -C 6 alkyl) groups, and -CD 3 ;
R 3 is chosen from hydrogen, C 1 -C 6 alkyl groups, C 1 -C 6 alkylalkoxy groups, C 1 -C 6 alkylamino groups, C 1 -C 6 alkylcarboxylic acid groups, C 1 -C 6 alkylhydroxy groups, C 3 -C 8 cycloalkyl groups, benzyl groups, C 3 -C 8 heterocyclyl groups, and —O—C(═O)—(C 1 -C 6 alkyl) groups;
R 4 is chosen from hydrogen, hydroxyl groups, —O—(C 1 -C 6 alkyl) groups, —O—C(═O)—(C 1 -C 6 alkyl) groups, and C 1 -C 6 alkyl groups; and
R 10 is chosen from 3 to 10 membered carbocycles and 3 to 10 membered heterocycles, each of which is substituted with 0 to 3 R 8 ,
wherein each R a is independently chosen from halogens, C 1 -C 6 alkyl groups, —O—(C 1 -C 6 )alkyl groups, C 1 -C 6 alkylalkoxy groups, C 1 -C 6 alkylhydroxy groups, -S(═O)w-(4 to 7 membered heterocycles) wherein w is 1 or 2, 4 to 7 membered carbocycles, hydroxyl groups, -NR 15 R 16 , C 3 -C 8 cycloalkyl groups, benzyl groups, and C 3 -C 8 heterocyclyl groups,
wherein each R 8 is independently substituted with 0 to 3 groups independently chosen from halogens, hydroxyl groups, -NR 15 R 16 , C 1 -C 6 alkyl groups, -(C═O)—(C 1 -C 6 alkyl) groups, -(C═O)—(C 1 -C 6 alkyl)(C 3 -C 10 heterocyclyl groups), -S(═O) w -(C 3 -C 8 heterocyclyl) groups wherein w is 0, 1, or 2, and C 1 -C 6 alkylcarboxylic acid groups, each of which is substituted with 0, 1, or 2 groups independently chosen from halogens, hydroxyl groups, -NR 15 R 16 , and C 1 -C 3 alkyl groups;
R 15 and R 16 are each independently chosen from hydrogen, R 17 , -C(═O)-R 17 , and —C(═O)—O-R 17 , wherein R 17 is chosen from hydrogen, C 1 -C 6 alkyl groups, C 3 -C 8 cycloalkyl groups, benzyl groups, and C 3 -C 8 heterocyclyl groups;
wherein R 1 , R 3 , R 4 , R 15 , R 16 , and R 17 are each independently substituted with 0 to 3 groups independently chosen from halogens, hydroxyl groups, C 1 -C 6 alkyl groups, —O—(C 1 -C 6 alkyl) groups, -NR 15 R 16 , C 3 -C 8 cycloalkyl groups, C 1 -C 6 alkylhydroxy groups, C 1 -C 6 alkylalkoxy groups, benzyl groups, and C 3 -C 8 heterocyclyl groups; and
L is a linker comprising at least one cleavable peptide moiety.
18. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein the at least one cleavable peptide moiety comprises valine-alanine (Val-Ala).
19. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein the at least one cleavable peptide moiety comprises valine-citrulline (Val-Cit), glutamic acid-valine-citrulline (Glu-Val-Cit), or alanine-alanine-asparagine (Ala-Ala-Asn).
20. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein the linker L comprising at least one cleavable peptide moiety comprises p-aminobenzyloxycarbonyl.
21. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein the linker L comprising at least one cleavable peptide moiety further comprises a polyethylene glycol moiety and/or an alkyl moiety.
22. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein the linker L comprising at least one cleavable peptide moiety further comprises maleimidocaproyl (MC).
23. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein the linker L comprising at least one cleavable peptide moiety is a compound of formula:
24. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein the linker L comprising at least one cleavable peptide moiety is a compound of formula: