Cleavable radioligands for targeting cell surface receptors and uses thereof
The present application relates to a compound or a pharmaceutically acceptable salt and/or solvate thereof comprising one or more circulation enhancing groups, one or more target binding groups, one or more chelating groups, at one least cleavable linker and at least one branching group that is at least trivalent. The application further includes a radionuclide complex or a pharmaceutically acceptable salt and/or solvate thereof, comprising a compound of the application or a pharmaceutically acceptable salt and/or solvate thereof, and one or more radionuclides, and to compositions comprising the compound or the complexes. The present application also includes methods of using the compounds, complexes and compositions for targeting and/or killing target cells. For example, the compound includes a compound of Formula I
1 . A compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof,
wherein
A is an albumin binding group selected from the group consisting of
unsubstituted or substituted C(O)C 1-26 alkyleneCO 2 H, unsubstituted or substituted C(O)C 2-26 alkenyleneCO 2 H, unsubstituted or substituted C(O)C 1-26 alkyl, and unsubstituted or substituted C(O)C 2-26 alkenyl;
Z is a tumor binding group, wherein the tumor binding group is a prostate specific membrane antigen (PSMA) binding group, a glucagon-like peptide-1 receptor (GLP-1R) binding group, or a glucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide; GIP) receptor (GIP-R) binding group;
E is a chelating group;
T is a branching group that is at least trivalent, wherein T is an amino acid residue derived from lysine, ornithine, homo-lysine, 2,3-diaminopropionic acid (DAP), 2,4-diaminobutyric acid (DAB), cysteine, homo-cysteine, glutamine, or trimesic acid (TMA);
L A and L E are each independently a direct bond, a cleavable linker or a non-cleavable linker, wherein the non-cleavable linker comprises one or more groups selected from one or more amino acids residues derived from Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Sec or PCL or the D enantiomers thereof; one or more amino acids residues derived from DAB or DAP; OEG, R 1 NC 1-20 alkyleneNR 2 , C(O)C 1-20 alkyleneC(O), R 1 NC 1-20 alkyleneC(O), and C(O)C 1-20 alkyleneNR 2 , wherein each R 1 and R 2 is independently selected from H and C 1-2 alkyl; and
L Z is a direct bond or a non-cleavable linker, wherein the non-cleavable linker comprises one or more of amino acid residues, R 1 NC 1-20 alkyleneNR 2 , R 1 NC 1-20 alkenyleneNR 2 , C(O)C 1-20 alkyleneC(O), C(O)C 1-20 alkenyleneC(O), R 1 NC 1-20 alkyleneC(O), R 1 NC 1-20 alkenyleneC(O), C(O)C 1-20 alkyleneNHR 2 , C(O)C 1-20 alkenyleneNR 2 , C(S)C 1-20 alkyleneC(S), C(S)C 1-20 alkenyleneC(S), C(S)C 1-20 alkyleneC(O), C(S)C 1-20 alkenyleneC(O), C(O)C 1-20 alkyleneC(S), C(O)C 1-20 alkenyleneC(S), C(O)C 1-20 alkyleneO, C(O)C 1-20 alkenyleneO, R 1 NC 1-20 alkenyleneC(S), C(S)C 1-20 alkyleneNR 2 and C(S)C 1-20 alkenyleneNR 2 , the latter 19 groups being optionally interrupted by one or more of S, O, NH, N(C 1-6 alkyl), C(O), C(O)NH, NHC(O), C(S)NH, NHC(S), NHC(O)NH, NHC(S)NH, NHC(NH), NHC(NC 1-4 alkyl), C(NH)NH, C(NC 1-4 alkyl)NH, NC 4-10 cycloalkyl, C 4-10 heterocycloalkyl, C 6-10 aryl and C 5-10 heteroaryl, and each alkyl, alkylene and alkenylene is optionally substituted with one or more substituents selected from halo, CO 2 H, C 1-6 alkyl, OH, OC 1-6 alkyl, SH, SC 1-6 alkyl, NR 3 R 4 , C 1-4 alkyleneOH, C 1-4 alkyleneOC 1-4 alkyl and C 1-4 alkyleneNR 3 R 4 , wherein each R 1 , R 2 , R 3 and R 4 is independently selected from H and C 1-4 alkyl; provided at least one of L A and L E is a cleavable linker, wherein the cleavable linker comprises at least one cleavable moiety, and the cleavable moiety is
wherein each
is a point of connection as set forth in the compound of Formula I.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein the albumin binding group is unsubstituted or substituted C(O)C 6-20 alkyleneCO 2 H.
3 . The compound of claim 2 , or a pharmaceutically acceptable salt or solvate thereof, wherein the albumin binding group is C(O)C 16 alkyleneCO 2 H or C(O)C 18 alkyleneCO 2 H.
4 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein the tumor binding group is a prostate specific membrane antigen (PSMA) binding group
5 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein the chelating group is selected from the group consisting of 1,4,7-Triazacyclononane (TACN); 1,4,7-triazacyclononane-triacetic acid (NOTA); 1,4,7-triazacyclononane-N-succinic acid-N′,N″-diacetic acid (NOTASA); 1,4,7-triazacyclononane-N-glutamic acid-N′,N″-diacetic acid (NODAGA); 1,4,7-triazacyclononane-N,N′,N″-tris (methylenephosphonic) acid (NOTP); 1,4,7,10-tetraazacyclododecane ([12]aneN4) (cyclen); 1,4,7,10-tetraazacyclotridecane ([13]aneN4); 1,4,7,11-tetraazacyclotetradecane (iso-cyclam); 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA); 2-(1,4,7,10-tetraazacyclododecan-1-yl) acetate (DO1A); 2,2′-(1,4,7,10-tetraazacyclododecane-1,7-diyl) diacetic acid (DO2A); 2,2′,2″-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (DO3A); 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methanepnosphonic acid) (DOTP); 1,4,7,10-tetraazacyclododecane-1,7-di(methanephosphoric acid) (DO2P); 1,4,7,10-tetraazacyclododecane-1,4,7-tri(methanephosphonic acid) (DO3P); 1,4,7,10-tetraazacyclo-decane-1-glutamic acid-4,7,10-triacetic acid (DOTAGA); 1,4,7,10-tetraazacyclodecane-1-succinic acid-4,7,10-triacetic acid (DOTASA); 1,4,8,11-tetraazacyclotetradecane ([14]aneN4) (cyclam); 1,4,8,12-tetraazacyclopentadecane ([15]aneN4); 1,5,9,13-tetraazacyclohexadecane ([16]aneN4); 1,4-ethano-1,4,8,11-tetraazacyclo-tetradecane (et-cyclam); 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA); 2-(1,4,8,1-tetraazacyclotetradecane-1-yl) acetic acid (TE1A); 2,2′-(1,4,8,11-tetraazacyclotetradecane-1,8-diyl) diacetic acid (TE2A); 4,11-bis(carboxy methyl)-1,4,8,11-tetraazabicyclo [6.6.2]-hexadecane (CB-TE2A); 3,6,10,13,16,19-hexaazabicyclo [6.6.6]icosane (Sar); 1,4,7,10-tetra-(2-carbamoyl-methyl)-cyclododecane (TCMC); N,N′-bis [(6-carboxy-2-pyridil) methyl]-4,13-diaza-18-crown-6 (macropa), phthalocyanines and derivatives thereof; and porphyrins and derivatives thereof.
6 . The compound of claim 5 , or a pharmaceutically acceptable salt or solvate thereof, wherein the chelating group is selected from the group consisting of DOTA and DOTAGA.
7 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein T is an amino acid residue derived from lysine, ornithine, homo-lysine, 2,3-diaminopropionic acid (DAP), 2,4-diaminobutyric acid (DAB), cysteine, homo-cysteine, or glutamine.
8 . The compound of claim 7 , or a pharmaceutically acceptable salt or solvate thereof, wherein T is an amino acid residue derived from lysine.
9 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein each non-cleavable linker of L Z independently comprises one or more groups selected from the group consisting of amino acid residues, R 1 NC 1-20 alkyleneNR 2 , C(O)C 1-20 alkyleneC(O), R 1 NC 1-20 alkyleneC(O), and C(O)C 1-20 alkyleneNR 2 , wherein the latter 4 groups being optionally interrupted by one or more of S, O, C(O)NH, NHC(O), NC 4 -6cycloalkyl, C 4-6 heterocycloalkyl, and each alkyl and alkylene is optionally substituted with one or more substituents selected from the group consisting of halo, CO 2 H, C 1-6 alkyl, OH, OC 1-6 alkyl, SH, SC 1-6 alkyl, NR 3 R 4 , C 1-4 alkyleneOH, C 1-4 alkyleneOC 1-4 alkyl and C 1-4 alkyleneNR 3 R, wherein each R 1 , R 2 , R 3 and R 4 is independently H or C 1-4 alkyl.
10 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein each cleavable linker independently comprises at least one cleavable moiety
and one or more groups selected from the group consisting of one or more amino acid residues, R 5 NC 1-20 alkyleneNR 6 , C(O)C 1-20 alkyleneC(O), R 5 NC 1-20 alkyleneC(O), C(O)C 1-20 alkyleneNR 6 , R 5 NC 1-20 alkyleneO, OC 1-20 alkyleneNR 6 , C(O)C 1-20 alkyleneO and OC 1-20 alkyleneC (O), wherein the latter 8 groups being optionally interrupted by one or more of S, O, C(O)NH, NHC(O), C 4-18 cycloalkyl, and C 4-10 heterocycloalkyl, and each alkyl and alkylene is optionally substituted with one or more substituents selected from the group consisting of halo, CO 2 H, NR 7 R 7 , and C 1-4 alkyleneNR 7 R 8 , wherein each R 5 , R 6 , R 7 and R 8 is independently H or C 1-4 alkyl, and wherein the amino acid residue is derived from an naturally occurring amino selected from the group consisting of alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine (Cys), glutamine (Gln), glutamic acid (Glu), glycine (Gly), histidine (His), isoleucine (Ile), leucine (Leu), Lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr), and valine (Val).
11 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein the cleavable linker comprises at least one group selected from the group consisting of
12 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein L A is a cleavable linker, and L E is a direct bond or a non-cleavable linker, wherein L A comprises at least one group selected from the group consisting of
13 . The compound of claim 12 , or a pharmaceutically acceptable salt or solvate thereof, wherein L E is a direct bond.
14 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein L E is a cleavable linker, and L A is a direct bond or a non-cleavable linker, wherein L E comprises at least one group selected from the group consisting of
15 . The compound of claim 14 , or a pharmaceutically acceptable salt or solvate thereof, wherein L A is a non-cleavable linker.
16 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein L Z further comprises one or more groups selected from the group consisting of one or more amino acids residues derived from Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, or Sec or the D enantiomers thereof; one or more amino acids residues derived from DAB or DAP;
R 1 NC 1-20 alkyleneNR 2 , C(O)C 1-20 alkyleneC (O), R 1 NC 1-20 alkyleneC (O), and C(O)C 1-20 alkyleneNR 2 , wherein each R 1 and R 2 is independently H or C 1-2 alkyl.
17 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein the albumin binding group is selected from the group consisting of 4-pIBA, C(O)C 15 alkyl, C(O)C 17 alkyl, C(O)C 15 alkyleneCO 2 H, C(O)C 16 alkyleneCO 2 H, C(O)C 17 alkyleneCO 2 H, and C(O)C 18 alkyleneCO 2 H.
18 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein the tumor binding group is a prostate specific membrane antigen (PSMA) binding group.
19 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein the tumor binding group is a PSMA binding group, and wherein the PSMA binding group is a peptide analogue selected from quisqualic acid, aspartate-glutamate (Asp-Glu), Glu-Glu, glycine-glutamate (Gly-Glu), γ-glutamate-glutamate (γ-Glu-Glu) and beta-N-acetyl-L-aspartate-L-glutamate (β-NAAG).
20 . A radionuclide complex, or a pharmaceutically acceptable salt or solvate thereof, comprising a compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and one or more radionuclides.
21 . The radionuclide complex of claim 20 , or a pharmaceutically acceptable salt or solvate thereof, wherein the one or more radionuclides are selected from the group consisting of 14 C, 15 N, 18 F, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I, 131 I, 35 S, 99 Tc, 99m Tc, 188 Re, 186 Re, 153 Sm, 67 Ga, 68 Ga, 111 In, 59 Fe, 63 Zn, 52 Fe, 45 Ti, 60 Cu, 61 Cu, 67 Cu, 64 Cu, 62 Cu, 82 Rb, 195m Pt, 191m Pt, 193m Pt, 117m Sn, 89 Zr, 177 Lu, 66 Ho, 86 Y, 87 Y, 90 Y, 89 Sr, 153 Gd, 225 Ac, 212 Bi, 213 Bi, 211 At, 198 Au, 199 Au, 193m Pt, 197 Pt, 103 Pd, 109 Pd, 105 Rh, 103m Rh, 223 Ra, 224 Ra, 97 Ru, 227 Th, 229 Th, 32 P, 161 Tb, 33 P, 149 Tb, 203 Pb, 212 Pb, 201 Tl, 119 Sb, 58m Co, 55 Co, 47 Sc, 149 Pm and 161 Ho.
22 . The radionuclide complex of claim 21 , or a pharmaceutically acceptable salt or solvate thereof, wherein the one or more radionuclides are selected from the group consisting of 111 In, 161 Tb, 64 Cu, 177 Lu, 212 Pb, and 225 Ac.