Chimeric small molecules for the recruitment of antibodies to cancer cells
The present invention relates to chimeric chemical compounds which are used to recruit antibodies to cancer cells, in particular, prostate cancer cells or metastasized prostate cancer cells. The compounds according to the present invention comprise an antibody binding terminus (ABT) moiety covalently bonded to a cell binding terminus (CBT) through a linker and optionally, a connector molecule.
1. A composition in pharmaceutical dosage form in combination with a pharmaceutically acceptable carrier, additive or excipient, comprising an anticancer effective amount of a compound according to the chemical structure:
Wherein each n is independently 1 or 2;
A is an antibody binding moiety according to the chemical structure:
Where Y′ is H or NO 2 ;
X is O, CH 2 , NR 1 , S(O), S(O) 2 , —S(O) 2 O, —OS(O) 2 , or OS(O) 2 O;
R 1 is H, a C 1 -C 3 alkyl group, or a —C(O)(C 1 -C 3 ) group;
X b is a bond, O, CH 2 , NR 1 or S;
B is a cell binding moiety according to the chemical formula:
Wherein X 1 and X 2 are each independently CH 2 , O, NH or S;
X 3 is O, CH 2 , NR 1 , S(O), S(O) 2 , —S(O) 2 O, —OS(O) 2 , or OS(O) 2 O;
R 1 is H, a C 1 -C 3 alkyl group, or a —C(O)(C 1 -C 3 ) group;
k is an integer from 1 to 10;
L is a linker according to the chemical formula:
Or L is a polyethylene glycol, polypropylene glycol or polypropylene-co-polyethylene glycol linker having between 1 and 20 glycol units;
Wherein R a is H, C 1 -C 3 alkyl or alkanol or together with R a forms a proline side chain with R 3 ;
R 3 forms a proline side chain with R a or R 3 is a side chain derived from an amino acid selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan and valine; and
Each m is independently an integer from 1 to 12; or
L is a linker according to the chemical formula:
Where Z and Z′ are each independently a bond, —(CH 2 ) i -O, —(CH 2 ) i -S, —(CH 2 ) i -N-R,
wherein said —(CH 2 )i group, if present in Z or Z′, is bonded to[CON], antibody binding terminus (ABT) or cell binding terminus (CBT);
Each R is independently H, or a C 1 -C 3 alkyl or alkanol group;
Each R 2 is independently H or a C 1 -C 3 alkyl group;
Each Y is independently a bond, O, S or N-R;
Each i is independently an integer from 0 to 15;
D is
or a bond,
with the proviso that Z, Z′ and D are not each simultaneously bonds;
j is an integer from 1 to 100;
m′ is an integer from 1 to 100;
n′ is an integer from 1 to 100; and
X″ is O, S or N-R,
R is as defined above; and
[CON] is a bond or a moiety according to the chemical structure:
Where X 2 is O, S, NR 4 , S(O), S(O) 2 , —S(O) 2 O, —OS(O) 2 , or OS(O) 2 O;
X 3 is NR 4 , O or S; and R 4 is H, a C 1 -C 3 alkyl or alkanol group, or a —C(O)(C 1 -C 3 ) group; or
a pharmaceutically acceptable salt thereof.
2. The composition according to claim 1 wherein A is
Where Y′ is H;
X is O, CH 2 , or NR 1 ; and
R 1 is H, a C 1 -C 3 alkyl group, or a —C(O)(C 1 -C 3 ) group; or
a pharmaceutically acceptable salt thereof.
3. The composition according to claim 1 wherein said linker is group according to the chemical formula:
Where R a is H or forms a proline side chain with R 3 and R 3 forms a proline side chain with R a or is a side chain derived from an amino acid selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan and valine; and
Each m is independently an integer from 1 to 12.
4. The composition according to claim 1 wherein [CON] is a
group,
where X 2 is O, S or NR 4 ; and
R 4 is H or a C 1 -C 3 alkyl group.
5. The composition according to claim 1 wherein said linker is a group according to the formula:
Wherein m is an integer from 1 to 8.
6. The composition according to claim 1 wherein A is
where X is O or NH;
L is a
group;
where m is an integer from 2 to 12; and
[CON] is attached to A or B through linker L.
7. The composition according to claim 1 according to the chemical structure:
Where n is an integer from 1 to 12; and
X is
Where Y N , Y N1 and Y′ is H or NO 2 ; with the proviso that at least two of Y N , Y N1 and Y′ is NO 2 , or a pharmaceutically acceptable salt thereof.
8. The composition according to claim 7 wherein X is
and Y′ is H or NO 2 .
9. The composition according to claim 8 wherein n is an integer from 1-8.
10. The composition according to claim 1 in combination with an additional anticancer agent.
11. The composition according to claim 2 in combination with an additional anticancer agent.
12. The composition according to claim 4 in combination with an additional anticancer agent.
13. The composition according to claim 10 wherein said additional anticancer agent is an antimetabolite, an inhibitor of topoisomerase I and II, an alkylating agent, a microtubule inhibitor or mixtures thereof.
14. The composition according to claim 11 wherein said additional anticancer agent is an antimetabolite, an inhibitor of topoisomerase I and II, an alkylating agent, a microtubule inhibitor or mixtures thereof.
15. The composition according to claim 12 wherein said additional anticancer agent is an antimetabolite, an inhibitor of topoisomerase I and II, an alkylating agent, a microtubule inhibitor or mixtures thereof.
16. The composition according to claim 1 in parenteral dosage form.
17. The composition according to claim 2 in parenteral dosage form.
18. The composition according to claim 16 wherein said parenteral dosage form is an intravenous dosage form.
19. The composition according to claim 17 wherein said parenteral dosage form is an intravenous dosage form.
20. A method of treating prostate cancer in a patient in need thereof comprising administering to said patient an effective amount of a composition according to claim 1 .
21. A method of treating prostate cancer in a patient in need thereof comprising administering to said patient an effective amount of a composition according to claim 2 .
22. A method of treating prostate cancer in a patient in need thereof comprising administering to said patient an effective amount of a composition according to claim 10 .
23. A method of treating prostate cancer in a patient in need thereof comprising administering to said patient an effective amount of a composition according to claim 11 .
24. A method of treating prostate cancer in a patient in need thereof comprising administering to said patient an effective amount of a composition according to claim 13 .
25. A method of treating prostate cancer in a patient in need thereof comprising administering to said patient an effective amount of a composition according to claim 14 .
26. A method of treating prostate cancer in a patient in need thereof comprising administering to said patient an effective amount of a composition according to claim 15 .
27. The method according to claim 20 wherein said prostate cancer is metastatic prostate cancer.
28. The method according to claim 21 wherein said prostate cancer is metastatic prostate cancer.
29. The method according to claim 22 wherein said prostate cancer is metastatic prostate cancer.
30. The method according to claim 23 wherein said prostate cancer is metastatic prostate cancer.