Synthetic antibody mimetic compounds (SYAMS) targeting cancer, especially prostate cancer
The present invention relates to compounds which function as antibody mimetic compounds. These compounds are bifunctional/multifunctional compounds which contain at least one cancer cell binding moiety which selectively binds to prostate specific membrane antigen (PSMA) and a FC receptor binding moiety which modulates an FC immune receptor, preferably a FcγRI receptor. Compounds according to the present invention bind selectively to cancer cells which upregulate PSMA and through that interaction, place the Fc receptor binding moiety of the compound in proximity to a Fc receptor, preferably a FcγRI receptor, which can modulate (preferably, upregulate) a humoral response in a patient to cancer cells. Through this biological action of the compounds according to the present invention, cancer cells, including metastatic cancer cells, especially prostate cancer cells can be immune regulated, resulting in the favorable therapy of cancer in a patient. Methods of using these compounds to treat cancer and/or reduce the likelihood of metastatis of cancer are additional aspects of the present invention.
1. A compound according to the chemical structure:
where [IBT] is an FcγRI receptor binding moiety according the chemical structure:
[CBT] is a cell binding moiety which binds to prostate specific membrane antigen (PSMA) according to the chemical structure:
Where 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 0 to 20;
L 1 and L 2 are each independently linker groups, each of which groups optionally includes one or more bifunctional connector groups [CON};
[MULTICON} is a multifunctional connector group which, when present, connects at least one [IBT) group to at least one [CBT] group through said linker group;
MCON is 0, 1, 2 or 3;
N″ and n′″ are each independently 1, 2, 3
NL1 and NL2 are each an integer from 0 to 5, with the proviso that n″≥NL1 and n′″≥NL2 and at least one of MCON, NL1 and NL2 is at least 1, or
a pharmaceutically acceptable salt or stereoisomer thereof.
2. The compound according to claim 1 wherein MCON is 1, 2 or 3.
3. The compound according to claim 1 wherein MCON is 1.
4. The compound according to claim 1 wherein n″ is 1, 2 or 3 and n′″ is 1 or 2.
5. The compound according to claim 1 wherein said [IBT] group is CP33.
6. The compound according to claim 2 wherein said [IBT] group is CP33.
7. The compound according to claim 3 wherein said [IBT] group is CP33.
8. The compound according to claim 1 wherein said [IBT] group is CP33.
9. The compound according to claim 1 wherein said [CBT] group is a group according to the chemical structure:
Where k is an integer from 0 to 20, or a salt or enantiomer thereof.
10. The compound according to claim 2 wherein said [CBT] group is a group according to the chemical structure:
Where k is an integer from 1 to 4, or a salt or enantiomer thereof.
11. The compound according to claim 3 wherein said [CBT] group is a group according to the chemical structure:
Where k is an integer from 1 to 4, or a salt or enantiomer thereof.
12. The compound according to claim 4 wherein said [CBT] group is a group according to the chemical structure:
Where k is an integer from 1 to 4, or a salt or enantiomer thereof.
13. The compound according to claim 5 wherein said [CBT] group is a group according to the chemical structure:
Where k is an integer from 1 to 4, or a salt or enantiomer thereof.
14. The compound according to claim 6 wherein said [CBT] group is a group according to the chemical structure:
Where k is an integer from 1 to 4, or a salt or enantiomer thereof.
15. The compound according to claim 7 wherein said [CBT] group is a group according to the chemical structure:
Where k is an integer from 1 to 4, or a salt or enantiomer thereof.
16. The compound according to claim 8 wherein said [CBT] group is a group according to the chemical structure:
Where k is an integer from 1 to 4, or a salt or enantiomer thereof.
17. The compound according to claim 4 wherein said [CBT] group is a group according to the chemical structure:
Where k is 4, or a salt or enantiomer thereof.
18. The compound according to claim 1 wherein at least one linker optionally contains a [CON] group 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 O, S or NR 4 ; and
R 4 is H, a C 1 -C 3 alkyl or alkanol group, or a —C(O)(C 1 -C 3 ) group.
19. The compound according to claim 1 wherein at least one linker optionally contains a [CON] group wherein said [CON] group is according to the chemical structure;
Where CL is
m is an integer from 0 to 12;
and iL is 0 or 1.
20. The compound according to claim 1 wherein said linker group L 1 or L 2 comprises polyethyleneglycol (PEG) linkages, polypropylene glycol linkages, or polyethyleneglycol-co-polypropylene polymers from 1 to 100 units in length;
a linker according to the structure:
Where R a is H, C 1 -C 3 alkyl, alkanol or forms a cyclic ring with R 3 in the case of proline and R 3 is a side chain derived from an amino acid;
m″ is an integer from 0 to 25; and
m is an integer from 1 to 100; wherein each of said groups is optionally further linked through amide groups, keto groups, amine groups or amino acids.
21. The compound according to claim 1 wherein said linker group L 1 or L 2 comprises or a linker according to the structure:
where R a is H or a C 1 -C 3 alkyl;
m is an integer from 1 to 12;
m″ is an integer 1, 2, 3, 4, 5, or 6;
t is 0, 1, 2, 3, 4, 5 or 6; and
iL is 0 or 1, wherein said linker optionally contains a [CON] group and is linked to a [CBT] group at one end optionally through said [CON] group and a [MULTICON] group on the other end; or
a linker according to the structure:
Where q is an integer from 0-12; and
q′ is 1 to 12; or
a linker according to the chemical structure:
Where q is an integer from 0-12; and
q′ is 1 to 12;
iL is 0 or 1; and
R L is an amino acid or an oligopeptide or a
linker according to the chemical structure:
where each X S is independently S, O or N—R S ;
R S is H or C 1 -C 3 alkyl;
S c is CH 2 ; CH 2 O; or CH 2 CH 2 O;
i is 0 or 1; and
m S is 0, 1, 2, 3, 4, 5, or 6, or 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 Z or Z′ group, is optionally bonded to another linker group, a connector group [CON], a [MULTICON] group, an IBT group or a CBT group;
each R is 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 0 to 100;
D is
or a bond, or
D may be
or a polypropylene glycol or polypropylene-co-polyethylene glycol linker having between 1 and 100 glycol units;
with the proviso that Z, Z′ and D are not each simultaneously bonds;
each i is independently 0 to 100;
j is 1 to 100;
m (within this context) is an integer from 1 to 100; and
n (within this context) is an integer from 1 to 100;
m′ is 1 to 100;
m″ is an integer between 0 to 25;
n′ is 1 to 100;
X 1 is O, S or N—R;
R is H, or a C 1 -C 3 alkyl or alkanol group; and
R a is H, C 1 -C 3 alkyl or alkanol or forms a cyclic ring with R 3 ; and R 3 is a side chain derived from an amino acid.
22. The compound according to claim 1 wherein said [MULTICON] group is a
multifunctional connector group or molecule according to the chemical structure:
where Y 4 is C—H or N; and
Each X″ is (CH 2 ) n″ O, (CH 2 ) n″ N RCON , (CH 2 ) n″ S,
(CH 2 ) n″ , (CH 2 ) n″ C═O or a [CON] group;
RCON is H or a C 1 -C 3 alkyl;
n″ is 0, 1, 2 or 3;
r is an integer from 1 to 12; and
said [CON] group, if present, is 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.
23. The compound according to claim 1 wherein L 1 and/or L 2 is a
group;
where R a is H or CH 3 ;
m is an integer from 1 to 12;
m″ is an integer 1, 2, 3, 4, 5, or 6;
t is 0, 1, 2, 3, 4, 5, or 6; and
iL is 0 or 1.
24. The compound according to claim 1 wherein L 1 and/or L 2 is
where R a is H;
m″ is 1, 2, 3, 4, 5 or 6 and
m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
25. The compound according to claim 1 wherein L 1 and/or L 2 is a polyethylene glycol linker between 1 and 12 glycol units in length or a polyethylene glycol linker extended to a second polyethylene glycol linker through a [CON] group, wherein said polyethylene glycol linker is from 1 to 12 glycol units in length and said second polyethylene glycol linker is from 1 to 12 glycol units in length.
26. The compound according to claim 25 wherein said [CON] group is
27. A compound according to the chemical structure:
Wherein each R ISY is independently H, a C 4 -C 12 alkyl group, an acyl group or a biotin group, and CP33 is a group according to the chemical structure:
or a pharmaceutically acceptable salt or stereoisomer thereof.
28. The compound according to claim 27 wherein R ISY is a biotin group.
29. The compound of claim 27 according to the chemical structure:
Wherein each R ISY is independently H, a C 4 -C 12 alkyl group, an acyl group or a biotin group, and CP33 is a group according to the chemical structure:
or a pharmaceutically acceptable salt or stereoisomer thereof.
30. The compound according to claim 29 wherein R ISY is a biotin group.
31. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 in combination with a pharmaceutically acceptable carrier, additive or excipient.
32. The composition according to claim 31 wherein said composition further comprises an effective amount of an anticancer agent other than a compound according to claim 1 .
33. The composition according to claim 32 wherein said other anticancer agent is an antimetabolite, an inhibitor of topoisomerase I and II, an alkylating agent, a microtubule inhibitor or mixtures thereof.
34. The composition according to claim 32 wherein said other anticancer agent is aldesleukin; alemtuzumab; alitretinoin; allopurinol; altretamine; amifostine; anastrozole; arsenic trioxide; asparaginase; BCG Live; bexarotene capsules; bexarotene gel; bleomycin; busulfan intravenous; busulfan oral; calusterone; capecitabine; carboplatin; carmustine; carmustine with polifeprosan 20 iplant; celecoxib; chlorambucil; cisplatin; cladribine; cyclophosphamide; cytarabine; cytarabine liposomal; dacarbazine; dactinomycin; darbepoetin alfa; daunorubicin liposomal; daunorubicin; denileukin diftitox; dexrazoxane; docetaxel; doxorubicin; doxorubicin liposomal; domostanolone propionate (drostanolone propionate); epirubicin; epoetin alfa estramustine; etoposide phosphate; etoposide (VP-16); exemestane; filgrastim; floxuridine (intraarterial); fludarabine; fluorouracil (5-FU); fulvestrant; gemtuzumab ozogamicin; goserelin acetate; hydroxyurea; Ibritumomab Tiuxetan; idarubicin; ifosfamide; imatinib mesylate; Interferon alfa-2a; Interferon alfa-2b; irinotecan; letrozole; leucovorin; levamisole; lomustine (CCNU); meclorethamine (nitrogen mustard); megestrol acetate; melphalan (L-PAM); mercaptopurine (6-MP); mesna; methotrexate; methoxsalen; mitomycin C; mitotane; mitoxantrone; nandrolone phenpropionate; nfetumomab (ofatumumab); LOddC; oprelvekin; oxaliplatin; paclitaxel; pamidronate; pegademase; Pegaspargase; Pegfilgrastim; pentostatin; pipobroman; plicamycin; mithramycin; porfimer sodium; procarbazine; quinacrine; Rasburicase; Rituximab; Sargramostim; streptozocin; telbivudine (LDT); talc; tamoxifen; temozolomide; teniposide (VM-26); testolactone; thioguanine (6-TG); thiotepa; topotecan; toremifene; Tositumomab; Trastuzumab; tretinoin (ATRA); Uracil Mustard; valrubicin; valtorcitabine (monoval LDC); vinblastine; vinorelbine; zoledronate; and mixtures thereof.
35. The composition according to claim 31 further comprising at least one antiandrogen compound.
36. The composition according to claim 31 further comprising at least one GNRh modulator.
37. The composition according to claim 31 further comprising at least one agent selected from the group consisting of flutamide, bicalutamide, nilutamide, cyproterone acetate, ketoconazole, aminoglutethimide, abarelix, leuprolide, goserelin, triptorelin, buserelin, abiraterone acetate, sorafenib and mixtures thereof.
38. The composition according to claim 31 further comprising at least one agent selected from the group consisting of an enlarged prostate agent; flutamide; goserelin; leuprolide; nilutamide; and mixtures thereof.
39. The composition according to claim 31 in oral dosage form.
40. The composition according to claim 31 in parenteral dosage form.
41. The composition according to claim 40 wherein said parenteral dosage form is an intravenous dosage form.
42. The composition according to claim 31 in topical dosage form.