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 (III):
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is chosen from absent, 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 2 is a linker L comprising at least one cleavable peptide moiety;
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 , R 5 , and R 8 are each independently 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;
R 6 and R 7 are each independently chosen from hydrogen, —O—R 17 , —O—C(═O)—R 17 , —O—C(═O)—NR 15 R 16 , C 1 -C 6 alkyl groups, and —NR 15 R 16 ;
R 15 and R 16 are each independently chosen from hydrogen, R 17 , —C(═O)—R 17 , and —C(═O)—O—R 17 ;
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; and
Z″ is chosen from
wherein R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , 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;
wherein at least one of R 6 and R 7 is hydrogen; and
wherein if Z″ is
and R 3 , R 6 , and R 7 are H and R 4 is methoxy and R 5 is hydroxyl, then R 1 is neither absent nor methyl.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
R 1 is chosen from absent, hydrogen, C 1 -C 4 alkyl groups, C 1 -C 4 alkylcarboxylic acid groups, C 1 -C 4 alkylhydroxy groups, and C 3 -C 8 cycloalkyl groups;
R 2 is a linker L comprising at least one cleavable peptide moiety;
R 3 is chosen from hydrogen, C 1 -C 4 alkyl groups, C 1 -C 4 alkylalkoxy groups, C 1 -C 4 alkylcarboxylic acid groups, and C 1 -C 4 alkylhydroxy groups;
R 4 is chosen from hydrogen, hydroxyl groups, —O—(C 1 -C 4 alkyl) groups, —O—C(═O)—(C 1 -C 4 alkyl) groups, and C 1 -C 4 alkyl groups;
R 5 is chosen from hydrogen, hydroxyl groups, —O—(C 1 -C 4 alkyl) groups, and C 1 -C 4 alkyl groups;
R 6 is chosen from hydrogen, —O—R 17 , —O—C(═O)—R 17 , and C 1 -C 4 alkyl groups;
R 7 is chosen from hydrogen, —O—R 17 , —O—C(═O)—R 17 , —O—C(═O)—NR 15 R 16 , C 1 -C 6 alkyl groups, and —NR 15 R 16 ;
R 8 is chosen from hydrogen, hydroxyl groups, —O—(C 1 -C 4 alkyl) groups, and C 1 -C 4 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 ;
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;
Z″ is chosen from
wherein R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , 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;
wherein at least one of R 6 and R 7 is hydrogen; and
wherein if Z″ is
and R 3 , R 6 , and R 7 are H and R 4 is methoxy and R 5 is hydroxyl, then R 1 is neither absent nor methyl.
3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
R 1 is chosen from absent, hydrogen, methyl, and C 1 -C 4 alkylcarboxylic acid groups;
R 2 is a linker L comprising at least one cleavable peptide moiety;
R 3 is chosen from hydrogen and C 1 -C 4 alkylcarboxylic acid groups;
R 4 is chosen from hydrogen, hydroxyl groups, —O—(C 1 -C 4 alkyl) groups, —O—C(═O)—(C 1 -C 4 alkyl) groups, and C 1 -C 4 alkyl groups;
R 5 is chosen from hydrogen and hydroxyl groups;
R 6 is hydrogen;
R 7 is hydrogen;
R 8 is chosen from hydrogen and hydroxyl groups; and
Z″ is chosen from
wherein R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 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, 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
wherein if R 3 , R 6 , and R 7 are H and R 4 is methoxy and R 5 is hydroxyl, then R 1 is neither absent nor methyl.
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. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
11. 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 .
12. The method of claim 11 , wherein the neoplastic disorder is a leukemia, a lymphoma, or a myeloma.
13. The method of claim 12 , wherein the myeloma is multiple myeloma.
14. 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 .
15. The compound of claim 1 , wherein the compound is chosen from a compound of formula
and
pharmaceutically acceptable salts thereof.
16. The compound of claim 1 , wherein the compound is chosen from a compound of formula
and
pharmaceutically acceptable salts thereof.
17. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the linker L comprising at least one cleavable peptide moiety further comprises at least one spacer unit.
18. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the at least one cleavable peptide moiety comprises valine-alanine (Val-Ala).
19. The compound of claim 1 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 1 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 1 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 1 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 1 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 1 or a pharmaceutically acceptable salt thereof, wherein the linker L comprising at least one cleavable peptide moiety is a compound of formula:
25. A compound of formula:
or
a pharmaceutically acceptable salt thereof,
wherein:
R 1 is chosen from absent, 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 2 is a linker L comprising at least one cleavable peptide moiety;
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(═O)—(C 1 -C 6 alkyl) groups, and C 1 -C 6 alkyl groups;
R 5 and R 8 are each independently 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;
R 6 and R 7 are each independently chosen from hydrogen, —O—R 17 , —O—C(═O)—R 17 , —O—C(═O)—NR 15 R 16 , C 1 -C 6 alkyl groups, and —NR 15 R 16 ;
R 15 and R 16 are each independently chosen from hydrogen, R 17 , —C(═O)—R 17 , and —C(═O)—O—R 17 ;
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; and
Z″ is chosen from
wherein R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , 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;
wherein at least one of R 6 and R 7 is hydrogen.