Therapeutic combinations

Abstract

The present invention relates to combinations comprising a PSMA binding compound and a MEK inhibitor, wherein the PSMA binding compound and the MEK inhibitor are as defined herein, kits and medicaments comprising them, and their use in the treatment, prevention, amelioration, control or reduction of risk of disorders associated with PSMA and / or MEK, including cancer, in particular prostate cancer.

Description

[0001] This invention relates to a combination of therapeutically effective compounds for use in various therapeutic areas associated with elevated expression of prostate-specific membrane antigen (PSMA), including the treatment and / or diagnosis of various cancers such as prostate cancer. Suitably, this invention relates to a combination of therapeutically effective compounds comprising: (i) a compound that binds to prostate-specific membrane antigen (hereinafter referred to as a PSMA-binding compound); and (ii) a compound that inhibits mitogen-activated protein kinase kinase MEK (hereinafter referred to as a MEK inhibitor), such as a MEK-1 inhibitor, a MEK-2 inhibitor, or a combination thereof. Suitably, this invention also relates to one or more therapeutic agents comprising (i) the combination of the PSMA-binding compound and (ii) the MEK inhibitor; and a kit comprising (i) the PSMA-binding compound and (ii) the MEK inhibitor. Suitablely, combinations of compounds comprising (i) the PSMA-binding compound and (ii) the MEK inhibitor, therapeutic agents comprising combinations of the compounds (i) and (ii), and kits comprising combinations of the compounds (i) and (ii) may each be used to treat (including preventive and curative treatments), prevent, improve, control, or reduce the risk of conditions (including cancers such as prostate cancer) associated with elevated expression of PSMA and / or MEK. Background Technology

[0002] Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein that is typically overexpressed on prostate cancer epithelial cells. Despite its name, PSMA is also expressed to varying degrees in the angiogenesis of various non-prostate cancers. Common non-prostate cancers that have demonstrated PSMA expression include breast cancer, colorectal cancer, and kidney cancer.

[0003] Prostate cancer (PCa) is a common malignant disease in men, with a high incidence and low survival rate. PSMA is overexpressed in prostate cancer (Silver et al., ...). Clinical Cancer Research 3, 81-85 (1997)), PSMA represents an excellent target for developing highly sensitive radiolabeling agents for internal radiotherapy and imaging of PCa (Afshar-Oromieh et al., European journal of nuclear medicine and molecular imaging 42, 197-209 (2015); Benešová et al., Journal of Nuclear Medicine 56, 914-920 (2015); Robu et al., Journal of Nuclear Medicine , 116.178939 (2016); Weineisen et al., Journal of Nuclear Medicine 55, 1083-1083 (2014); Rowe et al., Prostate cancer and prostatic diseases(2016); Maurer et al., Nature Reviews Urology (2016)).

[0004] PSMA is an extracellular hydrolase whose catalytic center contains two zinc(II) ions and a bridged hydroxyl ligand. It is highly upregulated in metastatic and hormone-refractory prostate cancer, but its physiological expression is also found in the kidneys, salivary glands, small intestine, and brain, and to a lesser extent in healthy prostate tissue. In the intestine, PSMA promotes folic acid absorption by converting pteroyl poly-γ-glutamate to pteroylglutamate (folic acid). In the brain, it hydrolyzes N-acetyl-L-aspartyl-L-glutamate (NAAG) to N-acetyl-L-aspartate and glutamate.

[0005] For example, already used 177 Lu-PSMA-617 demonstrates that PSMA-targeted radioligand therapy (PSMA-RLT) typically shows increased progression-free survival and overall survival in men with metastatic castration-resistant prostate cancer (mCRPC) (Sartor O, et al.). NEJM. 2021; 385: 1091–1103). 177 Lu-rhPSMA-10.1 is a PSMA-RLT reagent that typically exhibits low renal uptake, rapid blood clearance, and high tumor accumulation (Wurzer A et al., J Nucl Med. 2022; 63: 1489–1495). 177 Lu-rhPSMA-10.1 also typically exhibits effective inhibition of tumor growth in vivo (Foxton C et al., J Nucl Med. 2022; 63(Suppl 2): ​​abstract 2567), and showed promising efficacy in patients with mCRPC (Bundschuh RA et al., Clin Nucl Med. 2023; 48(4): 337–338). Other PSMA-binding (PSMA radiohybrid (rh)) compounds are disclosed in WO2019 / 020831, WO2020 / 157177, WO2020 / 157184, WO2022 / 144467, WO2022 / 144463 and WO2022 / 171901. Although PSMA-RLTs have generally shown improved progression-free survival in men with mCRPC, further methods to improve the efficacy of such agents are still needed.

[0006] The RAS-RAF-MEK-ERK signaling pathway is activated in many human tumors, mediating tumor growth, progression, and metastasis, and is therefore an attractive therapeutic target (Solit DB et al.). Nature 2006; 439: 358–362; Sebolt-Leopold JS et al., Nat Rev Cancer 2004; 4: 937–947). Although MEK itself is not an oncogene product, it is the focus of many signal transduction pathways activated by known oncogenes (including BRAF and KRAS mutations) and tyrosine kinase receptors (Ji H et al., 2004; 4: 937–947). Cancer Res. 2007; 67: 4933–4939). Therefore, inhibition of MEK may prevent subsequent downstream phosphorylation and activation of MAP kinases (to pMAPK / pERK), and thus induce tumor regression and / or arrest in some cases. Approved MEK inhibitors for clinical use include bemetinib (for melanoma), cobimetinib (for melanoma), selumetinib (for neurofibromatosis type 1), and trametinib (for melanoma). Other MEK inhibitors in clinical development include refatinib (BAY86-9766), WX-554, midametinib (PD-0325901), FCN-159, pimatetinib, CS3006, ARRY-300, tolametinib (HL-085), TAK-733, and MSC2015103B. Appropriately, MEK inhibitors have not been used to treat cancers associated with PSMA overexpression, such as prostate cancer.

[0007] It has been found that combinations of compounds comprising (i) PSMA-binding compounds as defined herein and (ii) MEK inhibitors as defined herein can provide therapeutic benefit for cancer, and appropriately for prostate cancer. Specifically, it has been found that when (i) PSMA-binding compounds as defined herein are used in combination with (ii) MEK inhibitors as defined herein, the combination of these compounds can provide a synergistic beneficial effect (i.e., a synergistic enhancement of therapeutic efficacy) in the treatment of cancer, and appropriately for prostate cancer, compared to the expected cumulative therapeutic efficacy that might be produced when the therapeutic efficacy of each compound (i) and (ii) is considered individually. Summary of the Invention

[0008] According to a first aspect, the present invention provides a combination of compounds comprising: (i) a compound capable of binding prostate-specific membrane antigens as defined herein (hereinafter referred to as a PSMA-binding compound); and (ii) a compound inhibiting mitogen-activated protein kinase kinase MEK as defined herein (hereinafter referred to as a MEK inhibitor), wherein the PSMA-binding compound comprises: (a) One or more ligands capable of binding PSMA; and (b) One or more chelating groups, wherein the one or more chelating groups contain chelated radioactive metal cations.

[0009] According to a second aspect, the present invention provides a combination of compounds (i) and (ii) as defined in the first aspect for medical use. Suitably, the combination of compounds (i) and (ii) as defined in the first aspect can be used to treat cancer, suitably for treating prostate cancer, suitably for treating hormone-sensitive prostate cancer, castration-resistant prostate cancer (CRPC), including metastatic CRPC and non-metastatic CRPC.

[0010] According to a third aspect, the present invention provides a therapeutic agent comprising a combination of compounds (i) and (ii) as defined in the first aspect, for medical use. Suitably, the therapeutic agent can be used to treat cancer, suitably for treating prostate cancer, suitably for treating hormone-sensitive prostate cancer, castration-resistant prostate cancer (CRPC), including metastatic CRPC and non-metastatic CRPC.

[0011] According to a fourth aspect, the present invention provides a kit comprising (i) a PSMA-binding compound as defined in the first aspect, and (ii) a MEK inhibitor as defined in the first aspect. Suitably, the kit can be used to treat cancer, suitably for treating prostate cancer, suitably for treating hormone-sensitive prostate cancer, castration-resistant prostate cancer (CRPC), including metastatic CRPC and non-metastatic CRPC.

[0012] Appropriately, the combination of compounds (i) and (ii) of the first aspect, the therapeutic agent of the third aspect, and the kit of the fourth aspect may each be used to treat (including preventive and curative treatment), prevent, improve, control, or reduce the risk of conditions associated with elevated expression of PSMA, MEK, or a combination of elevated expression of both PSMA and MEK.

[0013] Appropriately, the combination of compounds (i) and (ii) of the first aspect, the therapeutic agent of the third aspect, and the kit of the fourth aspect can each be used to treat non-prostate cancers, such as salivary gland cancer, thyroid cancer, hepatocellular carcinoma, glioblastoma, glioma, testicular cancer, breast cancer, lung cancer, colorectal cancer, or renal cell carcinoma.

[0014] According to the fifth aspect, methods for treating cancer are provided, which include administering to a patient in need a therapeutically effective amount of a combination of compounds (i) and (ii) of the first aspect, a therapeutic agent of the third aspect, or a kit of the fourth aspect. Appropriately, the cancer is prostate cancer. Appropriately, prostate cancer is hormone-sensitive prostate cancer, castration-resistant prostate cancer (CRPC), including metastatic CRPC and non-metastatic CRPC.

[0015] According to the sixth aspect, a method for treating cancer is provided, comprising administering to a patient in need a therapeutically effective amount of a combination of compounds (i) and (ii) of the first aspect, a therapeutic drug of the third aspect, or a kit of the fourth aspect, wherein the cancer is selected from salivary gland cancer, thyroid cancer, hepatocellular carcinoma, glioblastoma, glioma, testicular cancer, breast cancer, lung cancer, colorectal cancer, or renal cell carcinoma.

[0016] Appropriately, therapeutic administration of a combination of compounds (i) and (ii) of the first aspect, a therapeutic agent of the third aspect, or a kit of the fourth aspect to patients in need generally provides synergistically enhanced therapeutic efficacy in the treatment of cancer, and appropriately in the treatment of prostate cancer, compared to the expected cumulative therapeutic efficacy that may be produced when each compound (i) and (ii) is considered individually.

[0017] Appropriately, therapeutic administration to patients in need of a combination of compounds (i) and (ii) of the first aspect, a therapeutic agent of the third aspect, or a kit of the fourth aspect may increase the efficacy of (i) a PSMA-binding compound or (ii) a MEK inhibitor or (iii) both a MEK inhibitor and a PSMA-binding compound for the treatment of cancer.

[0018] Suitablely, in each aspect of the invention, (a) of the PSMA-binding compound (i) is capable of binding one or more ligands of PSMA comprising a structure represented by formula (1): (1).

[0019] Suitablely, the PSMA binding compound (i) as defined in each aspect of the invention also includes (c) a silicon-fluoride acceptor (SIFA) moiety as defined herein, which comprises a covalent bond between silicon and fluorine atoms.

[0020] Appropriately, when present, the silicon-fluoride acceptor (SIFA) portion (c) comprises the structure represented by equation (2): (2).

[0021] Suitablely, the fluorine atom in the silicon-fluoride acceptor (SIFA) moiety, as defined herein, can be used... 18 F-exchange. Appropriately, for the therapeutic applications disclosed herein, the fluorine atom in the silane-fluoride receptor (SIFA) moiety is... 19 F.

[0022] Suitably, in each aspect of the invention, one or more chelating groups of the PSMA-binding compound (i) as defined herein comprise residues of a chelating agent selected from 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA), α-(2-carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTAGA), and 1,4,7-triazacyclononane-1,4,7-tris[methylene(2-carboxyethyl)phosphonic acid] (TRAP).

[0023] Suitably, in each aspect of the invention, one or more chelating groups as defined herein contain chelated radioactive metal cations. Suitably, the chelated radioactive metal cations are selected from Sc. 3+ Cu 3+ Ga 3+ Y 3+ In 3+ 、Tb 3+ Ho 3+ Lu 3+ Re 3+ Pb 3+ Bi 3+ Ac 3+ Er 3+ and Th 3+ Appropriately, the radioactive metal cations are selected from... 64 Cu 3+ , 67 Cu 3+ , 149 Tb 3+ , 152 Tb 3+ , 155 Tb 3+ , 161 Tb 3+ , 225 Ac 3+ , 68 Ga 3+ and 177 Lu 3+ Appropriately, radioactive metal cations are 177 Lu 3+ or 225 Ac 3+ Preferred 177 Lu 3+ .

[0024] Suitablely, in each aspect of the invention, the PSMA-binding compound (i) is selected from: ; ; Or a pharmaceutically acceptable salt thereof, wherein M 3+ It is a chelated radioactive metal cation as defined herein. Appropriately, M 3+ yes 177 Lu 3+ or 225 Ac 3+ Preferred 177 Lu 3+ .

[0025] Suitablely, in each aspect of the invention, the PSMA-binding compound (i) is selected from: ; ; and its pharmaceutically acceptable salts, of which M 3+ It is a chelated radioactive metal cation as defined herein. Appropriately, M 3+ yes 177 Lu 3+ or 225 Ac 3+ Preferred 177 Lu 3+ .

[0026] In the embodiments, in each aspect of the invention, the PSMA-binding compound (i) is: ; Or its pharmaceutically acceptable salt.

[0027] Suitablely, in each aspect of the invention, the MEK inhibitor (ii) comprises a MEK-1 inhibitor, a MEK-2 inhibitor, or a combination of a MEK-1 inhibitor and a MEK-2 inhibitor.

[0028] Suitablely, in each aspect of the invention, the MEK inhibitor (II) is selected from: ; ; ; ; Or its pharmaceutically acceptable salt.

[0029] According to the implementation scheme, in each aspect of the invention, the MEK inhibitor (II) is: ; Or its pharmaceutically acceptable salt.

[0030] According to a preferred embodiment, in each aspect of the invention, the PSMA-binding compound (i) is: ; Or its pharmaceutically acceptable salt; and MEK inhibitor (ii) is: ; Or its pharmaceutically acceptable salt. Detailed Implementation

[0031] It should be understood that preferred features of each aspect of the invention are considered to be preferred features of each of the other aspects of the invention. Therefore, preferred and more preferred features of one aspect of the invention can be independently combined with other preferred and / or more preferred features of the same or different aspects of the invention.

[0032] Furthermore, it should be understood that any upper and lower limits, ranges, or ratio limits described herein can be combined independently.

[0033] This invention relates to novel combinations of compounds, kits and pharmaceuticals comprising said combinations of compounds. The invention also relates to the use of said novel combinations of compounds, kits and pharmaceuticals comprising said combinations of compounds in medicine, particularly in cancer treatment. The invention further relates to said combinations of compounds, kits and pharmaceuticals comprising said combinations of compounds for treating, preventing, improving, controlling, or reducing the risk of diseases or conditions associated with PSMA, MEK, or a combination of PSMA and MEK. The invention also relates to said combinations of compounds, kits and pharmaceuticals comprising said combinations of compounds for treating cancers with PSMA overexpression. The invention also relates to said combinations of compounds, kits and pharmaceuticals comprising said combinations of compounds for treating prostate cancer, salivary gland cancer, thyroid cancer, hepatocellular carcinoma, glioblastoma, glioma, testicular cancer, breast cancer, lung cancer, colorectal cancer, or renal cell carcinoma. Prostate cancer can be hormone-sensitive prostate cancer, castration-resistant prostate cancer (CRPC), including metastatic CRPC and non-metastatic CRPC.

[0034] This invention relates to combinations of compounds comprising (i) a PSMA-binding compound and (ii) a MEK inhibitor, wherein the PSMA-binding compound comprises: (a) One or more ligands capable of binding PSMA; and (b) One or more chelating groups, wherein the one or more chelating groups contain chelated radioactive metal cations.

[0035] It also provides drugs and kits containing PSMA-binding compounds and MEK inhibitors.

[0036] The PSMA-binding compounds described in this article, including combinations, drugs, and kits, may also include: (c) Silicon-fluoride acceptor (SIFA) portion, which consists of a covalent bond between silicon and fluorine atoms.

[0037] Therefore, combinations of compounds comprising (i) a PSMA-binding compound and (ii) a MEK inhibitor are also provided, wherein the PSMA-binding compound comprises the following: (a) One or more ligands that can bind PSMA; (b) one or more chelating groups, wherein the one or more chelating groups contain chelated radioactive metal cations; and (c) Silicon-fluoride acceptor (SIFA) portion, which consists of a covalent bond between silicon and fluorine atoms.

[0038] A complete kit containing (i) a PSMA-binding compound and (ii) a MEK inhibitor is also provided, wherein the PSMA-binding compound includes: (a) One or more ligands capable of binding PSMA; and (b) One or more chelating groups, wherein the one or more chelating groups contain chelated radioactive metal cations.

[0039] A complete kit containing (i) a PSMA-binding compound and (ii) a MEK inhibitor is also provided, wherein the PSMA-binding compound includes: (a) One or more ligands that can bind PSMA; (b) one or more chelating groups, wherein the one or more chelating groups contain chelated radioactive metal cations; and (c) Silicon-fluoride acceptor (SIFA) portion, which consists of a covalent bond between silicon and fluorine atoms.

[0040] Appropriately, in the kit, the PSMA-binding compound (i) is a separate physical entity from the MEK inhibitor (ii).

[0041] In the combinations, drugs, and kits described herein, the PSMA-binding compound can be a compound of formula (3): (3); Or its pharmaceutically acceptable salt, wherein: PSMA indicates a ligand that can bind to PSMA; L represents an optional substituted linking group; and CG represents a chelating group containing a chelated radioactive metal cation.

[0042] In the combinations, drugs, and kits described herein, the PSMA-binding compound may be a compound of formula (3'): (3'); Or its pharmaceutically acceptable salt, wherein: PSMA indicates a ligand that can bind to PSMA; L represents an optionally substituted linker group comprising a silicon-fluoride acceptor (SIFA) moiety, the SIFA moiety being contained in a covalent bond between silicon and fluorine atoms; and CG represents a chelating group containing a chelated radioactive metal cation.

[0043] In the combinations, drugs, and kits described herein, the ligands capable of binding PSMA may include any structure, part, or functional group capable of binding PSMA.

[0044] In the combinations, drugs, and kits described herein, ligands capable of binding PSMA may comprise structures represented by formula (1'): (1'); Where p is 1 to 6.

[0045] Preferably, p in formula (1') is 2. Appropriately, ligands capable of binding PSMA are obtained through formula (1') and formula (1) below. The labeled bond is linked to the remainder of the PSMA-binding compound. Appropriately, the PSMA-binding ligand is linked to the linking group L of compounds of formulas (3) and (3').

[0046] In the combinations, drugs, and kits described herein, ligands capable of binding PSMA may comprise structures represented by equation (1): (1).

[0047] In the combinations, drugs, and kits described herein, the PSMA-binding compound may be a compound of formula (1a): (1a); Or its pharmaceutically acceptable salt, wherein: L represents an optionally substituted linking group, preferably L represents an optionally substituted linking group comprising a silicon-fluoride acceptor (SIFA) moiety, the silicon-fluoride acceptor (SIFA) moiety being contained in a covalent bond between silicon and fluorine atoms; and CG represents a chelating group containing a chelated radioactive metal cation.

[0048] In the combinations, drugs, and kits described herein, the chelating group may include at least one of the following (i), (ii), or (iii): (i) A macrocyclic structure having 8 to 20 ring atoms, wherein 2 or more, more preferably 3 or more ring atoms are selected from oxygen or nitrogen atoms. Preferably, 6 or fewer ring atoms are selected from oxygen or nitrogen atoms. Particularly preferably, 3 or 4 ring atoms are nitrogen or oxygen atoms. Among oxygen and nitrogen atoms, nitrogen atoms are preferred. In conjunction with the macrocyclic structure, the preferred chelating group may comprise 2 or more, for example 2 to 6, preferably 2 to 4 carboxyl and / or hydroxyl groups. Among carboxyl and hydroxyl groups, carboxyl groups are preferred.

[0049] (ii) A non-cyclic, open-chain chelate structure having 8 to 20 main chain (backbone) atoms, wherein 2 or more, more preferably 3 or more main chain (backbone) atoms are heteroatoms selected from oxygen or nitrogen atoms. Preferably, 6 or fewer backbone atoms are selected from oxygen or nitrogen atoms. Among oxygen and nitrogen atoms, nitrogen atoms are preferred. More preferably, the open-chain chelate structure is a structure comprising a combination of 2 or more (more preferably 3 or more) heteroatoms selected from oxygen or nitrogen atoms and 2 or more (e.g., 2 to 6, preferably 2 to 4) carboxyl groups and / or hydroxyl groups. Among carboxyl and hydroxyl groups, carboxyl groups are preferred.

[0050] (iii) A branched chelate structure containing a quaternary carbon atom. Preferably, the quaternary carbon atom, except for the SIFA / ligand moiety, is substituted with three identical chelating groups. The substituted chelating groups may include amides. The substituted chelating groups may include aromatic groups. The substituted chelating groups may include hydroxypyridinones.

[0051] In the combinations, drugs, and kits described herein, the chelating group may include at least one of the following: (i) A macrocyclic structure having 8 to 20 ring atoms, wherein 2 or more ring atoms are heteroatoms selected from oxygen and nitrogen atoms; (ii) A non-cyclic, open-chain chelate structure having 8 to 20 main chain atoms, wherein two or more main chain atoms are heteroatoms selected from oxygen and nitrogen atoms; or (iii) Branched chelate structures containing quaternary carbon atoms.

[0052] In the combinations, pharmaceuticals, and kits described herein, the chelating group may comprise residues of a chelating agent selected from bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CBTE2a), cyclohexyl-1,2-diaminetetraacetic acid (CDTA), 4-(1,4,8,11-tetraazabicyclotetradecane-1-yl)-methylbenzoic acid (CPTA), N'-[5-[acetyl(hydroxy)amino]pentyl]-N-[5-[[4-[5-aminopentyl-(hydroxy)amino]-4-oxobutyryl]amino]pentyl]-N-hydroxybutyramide (DFO), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CBTE2a), cyclohexyl-1,2-diaminetetraacetic acid (CDTA), 4-(1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CBTE2a), cyclohexyl-1,2-diaminetetraacetic acid (CDTA), 4-(1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CDTA), cyclohexyl-1,2-diaminetetraacetic acid ... 6.6.2] Hexadecane (DO2A), 1,4,7,10-tetraazacyclododecane-N,N',N'',N''-tetraacetic acid (DOTA), α-(2-carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTAGA), 1,4,7,10-tetraazacyclododecane-N,N',N'',N''-1,4,7,10-tetra(methylene)phosphonic acid (DOTMP), N,N'-dipyridinoxyethylenediamine-N,N'-diacetate-5,5'-bis(phosphonate) (DPDP), diethylenetriamine-N,N',N''-penta(methylene)phosphonic acid (DTMP), diethylenetriamine-penta(ethylene)phosphonic acid DTPA (diethylamine-N,N'-tetraacetic acid), EDTA (ethylenediamine-N,N'-tetraacetic acid), EGTA (ethylene glycol-O,O-bis(2-aminoethyl)-N,N,N',N'-tetraacetic acid), HBED (N,N-bis(hydroxybenzyl)-ethylenediamine-N,N'-diacetic acid), HEDTA (hydroxyethyldiamine triacetic acid), HP-DOA3 (1-(p-nitrobenzyl)-1,4,7,10-tetraazacyclodecane-4,7,10-triacetic acid), HYNIC (6-hydrazino-N-methylpyridine-3-carboxamide), tetrakis(3-hydroxy-N-methyl-2-pyridone chelating agent) (4-((4-(3-(bis(2-(3-hydroxy-1-methyl-2-oxo-1, 2-Dihydropyridine-4-carboxamido)ethyl)amino)-2-((bis(2-(3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamido)ethyl)amino)methyl)propyl)phenyl)amino)-4-oxobutyric acid), abbreviated as Me-3,2-HOPO, 1,4,7-triazacyclononane-1-succinic acid-4,7-diacetic acid (NODASA), 1-(1-carboxy-3-carboxypropyl)-4,7-(carbonyloxy)-1,4,7-triazacyclononane (NODAGA), 1,4,7-triazacyclononanetriacetic acid (NOTA), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6].2] Hexadecane (TE2A), 1,4,8,11-tetraazacyclododecane-1,4,8,11-tetraacetic acid (TETA), tris(hydroxypyridinone) (THP), terpyridine-bis(methyleneaminetetraacetic acid) (TMT), 1,4,7-triazacyclononane-1,4,7-tris[methylene(2-carboxyethyl)phosphonic acid] (TRAP), 1,4,7,10-tetraazacyclotetrazane-N,N',N'',N''-tetraacetic acid (TRITA), 3-[[4,7-bis[[2-carboxyethyl(hydroxy)phosphoryl]methyl]-1,4,7-triazolonane-1-yl]methyl-hydroxy-phosphoryl]propionic acid, and triethylenetetraminehexaacetic acid (TTHA).

[0053] In the combinations, pharmaceuticals, and kits described herein, the chelating group may comprise residues of a chelating agent selected from 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA), α-(2-carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTAGA), and 1,4,7-triazacyclononane-1,4,7-tris[methylene(2-carboxyethyl)phosphonic acid] (TRAP).

[0054] In the combinations, pharmaceuticals, and kits described herein, the chelating group may comprise residues selected from the following chelating agents: ; ;and .

[0055] Particularly preferably, the chelating group comprises a chelating agent selected from DOTA and DOTAGA, which is connected to the remainder of the conjugate via an amide bond through one of its carboxyl groups.

[0056] In the combinations, drugs, and kits described herein, the optional silicon-fluoride acceptor (SiFA) moiety (c) may comprise a structure represented by formula (2'): (2'); Where R 1S and R 2S Independently, it is either a straight chain or a branched chain C. 3-10 alkyl; R 3S It is a C that contains one or more aromatic and / or aliphatic units. 1-20 hydrocarbon group; q is between 0 and 3; and, the SIFA part is obtained by using The key marked is connected to L.

[0057] Appropriately, R 1S and R 2SEach is independently selected from isopropyl and tert-butyl. Preferably, R 1S and R 2S They are the same. Appropriately, R 1S and R 2S All are tert-butyl. Appropriately, R 3S It is a C containing an aromatic ring. 6-10 Hydrocarbon group; preferably, R 3S Including a benzene ring; more preferably, R 3S It is a benzene ring in which the Si-containing substituent and amide group are in the para position relative to each other. Suitably, q can be 0, 1, 2 or 3. Preferably, q is 1. The SIFA moiety is formed by the expression in formulas (2), (2'), (2'') and (2'''). The labeled bond is linked to the rest of the PSMA-bound compound.

[0058] In the combinations, drugs, and kits described herein, the silicon-fluoride acceptor (SiFA) moiety may comprise a structure represented by formula (2''): (2''); Where q is between 0 and 3.

[0059] In the combinations, drugs, and kits described herein, the silicon-fluoride acceptor (SiFA) moiety may comprise a structure represented by formula (2'''): (2''').

[0060] In the context of combinations, drugs, and kits discussed herein, F should be understood to include... 19 F and 18 F. The fluorine atom in the silicon-fluoride acceptor (SIFA) portion can be... 19 F. The fluorine atom in the silicon-fluoride acceptor (SIFA) portion can be... 18 F. 18 F can be used in diagnostic applications, such as in positron emission tomography (PET) imaging. And... 19 F may exist where it is not needed. 18 In the case of F imaging, preferably, the fluorine atom in the silicon-fluoride acceptor (SIFA) portion is... 19 F.

[0061] In the combinations, drugs, and kits described herein, the silicon-fluoride acceptor (SiFA) portion may comprise a structure represented by equation (2): (2).

[0062] Suitablely, a silicon-fluoride acceptor (SIFA) portion comprising the structure represented by formula (2) can be obtained by using a silicon-fluoride acceptor (SIFA) portion comprising the structure represented by formula (2'') or (2''').

[0063] Suitable combinations are provided comprising (i) a PSMA-binding compound and (ii) a MEK inhibitor, wherein the PSMA-binding compound comprises: (a) One or more ligands capable of binding PSMA, comprising the structure represented by equation (1): (1); (b) One or more chelating groups, wherein the one or more chelating groups contain a chelated radioactive metal cation, and wherein the chelating group is selected from 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA), α-(2-carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTAGA), and 1,4,7-triazacyclononane-1,4,7-tris[methylene(2-carboxyethyl)phosphonic acid] (TRAP); and (c) The silicon-fluoride acceptor (SIFA) portion, which comprises the structure represented by equation (2): (2).

[0064] Suitable combinations are provided comprising (i) a PSMA-binding compound and (ii) a MEK inhibitor, wherein the PSMA-binding compound comprises: (a) A ligand capable of binding PSMA, comprising the structure represented by equation (1): (1); (b) a 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) chelating group containing a chelated radioactive metal cation; and (c) The silicon-fluoride acceptor (SIFA) portion, which comprises the structure represented by equation (2): (2).

[0065] Appropriately, kits comprising (i) a PSMA-binding compound and (ii) a MEK inhibitor are provided, wherein the PSMA-binding compound comprises: (a) One or more ligands capable of binding PSMA, comprising the structure represented by equation (1): (1); (b) One or more chelating groups, wherein the one or more chelating groups contain a chelated radioactive metal cation, wherein the chelating group is selected from 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA), α-(2-carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTAGA) and 1,4,7-triazacyclononane-1,4,7-tris[methylene(2-carboxyethyl)phosphonic acid] (TRAP); and (c) The silicon-fluoride acceptor (SIFA) portion, which comprises the structure represented by equation (2): (2).

[0066] Appropriately, kits comprising (i) a PSMA-binding compound and (ii) a MEK inhibitor are provided, wherein the PSMA-binding compound comprises: (a) A ligand capable of binding PSMA, comprising the structure represented by equation (1): (1); (b) a 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) chelating group containing a chelated radioactive metal cation; and (c) The silicon-fluoride acceptor (SIFA) portion, which comprises the structure represented by equation (2): (2).

[0067] In the compounds of formulas (1a), (3), and (3') described herein, group L may be an optionally substituted linking group comprising one or more amide bonds, oligoamide bonds, or oligo(ester-amide) bonds. Suitable linking groups L include those described and exemplified in WO2019 / 020831, WO2020 / 157177, and WO2020 / 157184. Suitably, linking group L may be an optionally substituted linking group comprising one or more amide bonds and comprising an optional silicon-fluoride acceptor (SIFA) moiety, which, when present, comprises a covalent bond between silicon and fluorine atoms. Suitably, linking group L may be an optionally substituted oligoamide or oligo(ester-amide) and comprising an optional silicon-fluoride acceptor (SIFA) moiety, which, when present, comprises a covalent bond between silicon and fluorine atoms.

[0068] In the compounds of formulas (1a), (3) and (3') described herein, the L-CG group can be selected from: ;as well as .

[0069] In the compounds of formulas (1a), (3) and (3') described herein, the CG group can be selected from: ; ; ; ; ; ; ; ; .

[0070] Suitablely, the chelated radioactive metal cation of the chelating group may chelate with one or more O atoms. Suitablely, the chelated radioactive metal cation of the chelating group may chelate with one or more N atoms. Suitablely, the chelated radioactive metal cation of the chelating group may chelate with one or more N atoms and / or one or more O atoms. In the case of chelated radioactive metal cations, the functional groups of the molecule are only representatively shown as negatively charged to balance the total charge (i.e., it should be understood that a negative charge can be present at any feasible position in the molecule).

[0071] In the PSMA-binding compounds described in this paper, the chelated radioactive metal cation (which may be referred to as M in this paper) 3+ The cation can be selected from Sc, Cu, Ga, Y, In, Tb, Ho, Lu, Re, Pb, Bi, Ac, Er, and Th. Suitablely, M... 3+ Can be selected from Sc 3 + Cu 3+ Ga 3+ Y 3+ In 3+ 、Tb 3+ Ho 3+ Lu 3+ Re 3+ Pb 3+ Bi 3+ Ac 3+ Er 3+ and Th 3+ .

[0072] Suitable, the chelating group may contain a component selected from Cu. 3+ 、Tb 3+ Ac 3+ Ga 3+ and Lu 3+ The chelated radioactive metal cation. Suitablely, the chelating group may contain chelated Ac... 3+ Cations, for example225 Ac 3+ Appropriately, the chelating group may contain chelated Ga. 3+ Cations, for example 68 Ga 3+ Appropriately, the chelating group may contain chelated Lu. 3+ Cations, for example 177 Lu 3 + Appropriately, radioactive Lu is preferred. 3+ Cations, especially 177 Lu 3+ .

[0073] Suitable, the chelating group may contain a selection from... 62 Cu、 64 Cu、 67 Cu、 68 Ga、 90 Y、 111 In、 149 Tb, 152 Tb, 155 Tb, 161 Tb, 166 Ho、 177 Lu、 186 Re、 188 Re、 212 Pb, 212 Bi、 213 Bi、 225 Ac and 227 Th chelated radioactive metal cations. Suitablely, the chelated radioactive metal cations are selected from... 62 Cu、 64 Cu、 67 Cu 、149 Tb, 152 Tb, 155 Tb, 161 Tb, 68 Ga、 177 Lu and 225 Ac cations. Appropriately, radioactive metal cations are selected from... 68 Ga、 177 Lu and 225 Ac. Chelating groups can contain chelating... 177 Lu cation. The chelating group may contain chelated... 225 Ac cation. The chelating group may contain chelating... 68 Ga cations. In a preferred embodiment of each aspect of the invention, the chelating group contains chelated... 177 Lu cation.

[0074] Suitable, the chelating group may contain a selection from... 62 Cu 3+ , 64 Cu 3+ , 67 Cu 3+ , 68 Ga 3+ , 90 Y 3+ , 111 In 3+ , 149 Tb 3+ , 152 Tb 3+ , 155 Tb 3+ , 161 Tb 3+ , 166 Ho 3+ , 177 Lu 3+ , 186 Re 3+ , 188 Re 3+ , 212 Pb 3+ , 212 Bi 3+ , 213 Bi 3+ , 225 Ac 3+ and 227 Th 3+ The chelated radioactive metal cation. The chelating group may contain a selection from... 62 Cu 3+ , 64 Cu 3+ , 67 Cu 3+ , 149 Tb 3+ , 152 Tb 3+ , 155 Tb 3+ , 161 Tb 3+ , 225 Ac 3+ , 68 Ga 3+ and 177 Lu 3+ The chelated radioactive metal cations. Suitable, the radioactive metal cations are selected from... 225 Ac 3+ , 68 Ga 3+ and 177 Lu 3+ The chelating group can contain chelating...177 Lu 3+ Cation. The chelating group may contain chelating... 225 Ac 3+ Cation. The chelating group may contain chelating... 68 Ga 3+ Cation. In a preferred embodiment of each aspect of the invention, the chelating group contains chelated... 177 Lu 3+ cation.

[0075] In the combinations, drugs, and kits described herein, the PSMA-binding compounds may be selected from: ; ; ; ; ; ; ; and its pharmaceutically acceptable salts, wherein M is a chelated radioactive metal cation as defined herein, for example, 177 Lu 3+ or 225 Ac 3+ The preferred option is 177 Lu 3+ .

[0076] In the combinations, drugs, and kits described herein, the PSMA-binding compounds may be selected from: ; ; ; ; ; ; ; and its pharmaceutically acceptable salts, wherein M is a chelated radioactive metal cation as defined herein, for example, 177 Lu 3+ or 225 Ac 3+ The preferred option is 177 Lu 3+ .

[0077] In the combinations, drugs, and kits described herein, the PSMA-binding compounds may be selected from: ; ; and its pharmaceutically acceptable salts, wherein M is a chelated radioactive metal cation as defined herein, for example, 177 Lu 3+ or 225 Ac 3+ The preferred option is 177 Lu 3+ .

[0078] In the combinations, drugs, and kits described herein, the PSMA-binding compounds may be selected from: ; ; and its pharmaceutically acceptable salts, wherein M is a chelated radioactive metal cation as defined herein, for example, 177 Lu 3+ or 225 Ac 3+ The preferred option is 177 Lu 3+ .

[0079] In the combinations, drugs, and kits described herein, the PSMA-binding compounds may be: ; Or its pharmaceutically acceptable salt.

[0080] Alternatively, in the combinations, drugs, and kits described herein, the PSMA-binding compounds may be selected from: ; ; ; ; ; ; and its pharmaceutically acceptable salts, wherein M is a chelated radioactive metal cation as defined herein, for example, 177 Lu 3+ or 225 Ac 3+ The preferred option is 177 Lu 3+ .

[0081] In the combinations, drugs and kits described herein, the MEK inhibitor can be any compound capable of inhibiting mitogen-activated protein kinase (MAPK) kinases MEK1 and / or MEK2.

[0082] In the combinations, drugs, and kits described herein, MEK inhibitors may be selected from: bemettinib, cobimetinib, selumetinib, trametinib, refatinib (BAY86-9766), WX-554, midametinib (PD-0325901), FCN-159, pimatetinib, CS3006, ARRY-300, tolametinib (HL-085), TAK-733, MSC2015103B, and their pharmaceutically acceptable salts.

[0083] In the combinations, drugs and kits described herein, MEK inhibitors may be selected from: bemettinib, cobimetinib, selmetinib, trametinib and their pharmaceutically acceptable salts.

[0084] In the combinations, drugs, and kits described in this article, MEK inhibitors may be selected from: ; ; ; ; ; ; ; ; Or its pharmaceutically acceptable salt.

[0085] In the combinations, drugs, and kits described in this article, MEK inhibitors may be selected from: ; ; ; ; Or its pharmaceutically acceptable salt.

[0086] In the combinations, drugs, and kits described herein, MEK inhibitors can be: ; Or its pharmaceutically acceptable salt.

[0087] In the combinations, drugs, and kits described herein, the MEK inhibitor may be cobimetinib or a pharmaceutically acceptable salt thereof.

[0088] In the combinations, drugs, and kits described herein, the PSMA-binding compounds may be: ; Or its pharmaceutically acceptable salt; And MEK inhibitors can be: ; Or its pharmaceutically acceptable salt.

[0089] Suitable combinations of compounds are provided, comprising: ; Or its pharmaceutically acceptable salt; as well as ; Or its pharmaceutically acceptable salt.

[0090] Appropriately, complete kits are provided, which include: ; Or its pharmaceutically acceptable salt; as well as ; Or its pharmaceutically acceptable salt.

[0091] The combinations, kits, and drugs described herein can be used to treat cancer. The combinations, kits, and drugs described herein can be used to treat cancers with PSMA overexpression. Methods for treating cancer are also provided, which include administering the combinations or drugs described herein to patients in need.

[0092] The combinations, drugs, and kits described herein can be used to treat prostate cancer, salivary gland cancer, thyroid cancer, hepatocellular carcinoma, glioblastoma, glioma, testicular cancer, breast cancer, lung cancer, colorectal cancer, or renal cell carcinoma. Methods for treating prostate cancer, salivary gland cancer, thyroid cancer, hepatocellular carcinoma, glioblastoma, glioma, testicular cancer, breast cancer, lung cancer, colorectal cancer, or renal cell carcinoma are also provided, comprising administering the combinations, kits, or drugs described herein to patients in need.

[0093] The combinations, kits, and drugs described herein can be used to treat cancer. Specifically, they can be used to treat prostate cancer, which can be metastatic or non-metastatic. These combinations, kits, and drugs can be used to treat prostate cancer, including hormone-sensitive prostate cancer and castration-resistant prostate cancer (CRPC), encompassing both metastatic and non-metastatic CRPC.

[0094] Methods for treating prostate cancer, including administering the combination, kit, or drug as described herein to patients in need, are also provided. These methods include treating hormone-sensitive prostate cancer, castration-resistant prostate cancer (CRPC), including metastatic CRPC and non-metastatic CRPC, and involve administering the combination, kit, or drug as described herein to patients in need.

[0095] Also provided are PSMA-binding compounds or pharmaceutically acceptable salts thereof as defined herein, for the treatment of cancer, wherein the PSMA-binding compound comprises: (a) One or more ligands capable of binding PSMA; and (b) One or more chelating groups, wherein the one or more chelating groups contain chelated radioactive metal cations; The treatment described herein includes administration of the PSMA-binding compound, and simultaneous, separate, or sequential administration of a MEK inhibitor as defined herein, or a pharmaceutically acceptable salt thereof.

[0096] PSMA-binding compounds are also provided: ; Or a pharmaceutically acceptable salt thereof, used for the treatment of cancer, wherein said treatment includes administration of the PSMA-binding compound, and concurrent, separate or sequential administration of a MEK inhibitor as defined herein, or a pharmaceutically acceptable salt thereof.

[0097] PSMA-binding compounds are also provided: ; Or a pharmaceutically acceptable salt thereof, used to treat cancer, wherein said treatment comprises administration of the PSMA-binding compound, and concurrent, separate, or sequential administration of a MEK inhibitor compound: ; Or its pharmaceutically acceptable salt.

[0098] Also provided are PSMA-binding compounds or pharmaceutically acceptable salts thereof as defined herein, for the treatment of prostate cancer, wherein the PSMA-binding compound comprises: (a) One or more ligands capable of binding PSMA; and (b) One or more chelating groups, wherein the one or more chelating groups contain chelated radioactive metal cations; The treatment described herein includes administration of the PSMA-binding compound, and simultaneous, separate, or sequential administration of a MEK inhibitor as defined herein, or a pharmaceutically acceptable salt thereof.

[0099] PSMA-binding compounds are also provided: ; Or a pharmaceutically acceptable salt thereof, for the treatment of prostate cancer, wherein said treatment comprises administration of the PSMA-binding compound, and concurrent, separate or sequential administration of a MEK inhibitor as defined herein, or a pharmaceutically acceptable salt thereof.

[0100] PSMA-binding compounds are also provided: ; Or a pharmaceutically acceptable salt thereof, used to treat prostate cancer, wherein said treatment comprises administration of the PSMA-binding compound, and concurrent, separate, or sequential administration of a MEK inhibitor compound: ; Or its pharmaceutically acceptable salt.

[0101] Methods for treating cancer are also provided, which include administering to patients in need a PSMA-binding compound as defined herein or a pharmaceutically acceptable salt thereof, wherein the PSMA-binding compound comprises: (a) One or more ligands capable of binding PSMA; and (b) One or more chelating groups, wherein the one or more chelating groups contain chelated radioactive metal cations; The treatment described herein includes simultaneous, separate, or sequential administration of a MEK inhibitor as defined herein, or a pharmaceutically acceptable salt thereof.

[0102] It also provides methods for treating cancer, which include administering the following compounds to patients in need: ; Or a pharmaceutically acceptable salt thereof, wherein the treatment comprises simultaneous, separate or sequential administration of a MEK inhibitor as defined herein, or a pharmaceutically acceptable salt thereof.

[0103] It also provides methods for treating cancer, which include administering the following compounds to patients in need: ; Or a pharmaceutically acceptable salt thereof, wherein the treatment comprises simultaneous, separate or sequential administration of a MEK inhibitor compound: ; Or its pharmaceutically acceptable salt.

[0104] Methods for treating prostate cancer are also provided, which include administering to patients in need a PSMA-binding compound as defined herein or a pharmaceutically acceptable salt thereof, wherein the PSMA-binding compound comprises: (a) One or more ligands capable of binding PSMA; and (b) One or more chelating groups, wherein the one or more chelating groups contain chelated radioactive metal cations; The treatment described herein includes simultaneous, separate, or sequential administration of a MEK inhibitor as defined herein, or a pharmaceutically acceptable salt thereof.

[0105] It also provides methods for treating prostate cancer, which include administering the following compounds to patients in need: ; Or a pharmaceutically acceptable salt thereof, wherein the treatment comprises simultaneous, separate or sequential administration of a MEK inhibitor as defined herein, or a pharmaceutically acceptable salt thereof.

[0106] It also provides methods for treating prostate cancer, which include administering the following compounds to patients in need: ; Or a pharmaceutically acceptable salt thereof, wherein the treatment comprises simultaneous, separate or sequential administration of a MEK inhibitor compound: ; Or its pharmaceutically acceptable salt.

[0107] The cancer can be prostate cancer, salivary gland cancer, thyroid cancer, hepatocellular carcinoma, glioblastoma, glioma, testicular cancer, breast cancer, lung cancer, colorectal cancer, or renal cell carcinoma. Preferably, the cancer is prostate cancer. Prostate cancer can be hormone-sensitive prostate cancer or castration-resistant prostate cancer (CRPC), including metastatic CRPC and non-metastatic CRPC.

[0108] Prostate cancer can be hormone-sensitive prostate cancer or castration-resistant prostate cancer (CRPC), including metastatic CRPC and non-metastatic CRPC.

[0109] Compared to the expected cumulative therapeutic efficacy that may result from combined use (considering the therapeutic efficacy of each compound (i) and (ii) individually), a synergistic enhancement of therapeutic efficacy can be observed in the combinations, kits, medicines, and related medical uses and methods described herein, in the treatment of cancer, and appropriately in the treatment of prostate cancer.

[0110] Increased potency of (i) a PSMA-binding compound or (ii) a MEK inhibitor or (iii) both a MEK inhibitor and a PSMA-binding compound can be observed in the combinations, kits, medicines and related medical uses and methods described herein.

[0111] Appropriately, combinations, drugs, or kits as described herein are provided for the treatment of cancer, and appropriately for the treatment of prostate cancer, wherein therapeutic administration comprising a combination of (i) a PSMA-binding compound as defined herein and (ii) a MEK inhibitor as defined herein provides a synergistic enhancement of therapeutic efficacy in the treatment of cancer, and appropriately for the treatment of prostate cancer, compared to the expected cumulative therapeutic efficacy that the combination may produce (considering the therapeutic efficacy of each compound (i) and (ii) individually).

[0112] Appropriately, combinations, drugs, or kits as described herein are provided for the treatment of cancer, wherein the therapeutic administration of a combination comprising (i) a PSMA-binding compound as defined herein and (ii) a MEK inhibitor as defined herein provides an increase in the potency of (i) the PSMA-binding compound or (ii) the MEK inhibitor or (iii) both the MEK inhibitor and the PSMA-binding compound.

[0113] In the combinations, kits, pharmaceuticals, and related medical uses and methods described herein, the PSMA-binding compound and MEK inhibitor may be as defined anywhere herein. In the combinations, kits, pharmaceuticals, medical uses, and methods described herein, the PSMA-binding compound and MEK inhibitor may be administered via any feasible route of administration. In some embodiments, the MEK inhibitor may be administered orally, and the PSMA-binding compound may be administered intravenously. The PSMA inhibitor and MEK inhibitor may be administered simultaneously, separately, or sequentially. The combinations, kits, pharmaceuticals, medical uses, and methods described herein are not limited to a single PSMA-binding compound and a single MEK inhibitor. Therefore, combinations, kits, and pharmaceuticals may comprise one or more different PSMA-binding compounds and one or more different MEK inhibitors. Medical uses and methods may also include the use of one or more different PSMA-binding compounds and one or more different MEK inhibitors.

[0114] PSMA-binding compounds and MEK inhibitors can be administered in any amount or regimen sufficient to achieve the desired therapeutic effect. Administration of the PSMA-binding compound and MEK inhibitor can be sequential, separate, or simultaneous. Administration may include a single dose of the PSMA-binding compound and a once-daily dose of the MEK inhibitor, wherein the PSMA-binding compound and the first dose of the MEK inhibitor are administered on the same day. Administration of the MEK inhibitor may continue until the desired therapeutic effect is achieved. The first dose of the MEK inhibitor may be administered shortly before the PSMA-binding compound.

[0115] definition In this application, unless otherwise stated, the following definitions apply.

[0116] The term "PSMA-binding compound" refers to a compound capable of binding to prostate-specific membrane antigen (PSMA) expressed in mammalian (particularly human) tissues. Exemplary PSMA-binding compounds are identified herein and / or disclosed in WO2019 / 020831, WO2020 / 157177 and WO2020 / 157184.

[0117] The term "MEK inhibitor" refers to a compound that can bind to and modulate the activity of mitogen-activated protein kinase (MAPK) kinases MEK1 and / or MEK2.

[0118] When using the term "combination" or "combination of compounds," it should be understood that this can refer to the components of the combination being administered simultaneously, separately, or sequentially. For the avoidance of ambiguity, it should be understood that the components of a combination, such as (i) a PSMA-binding compound and (ii) a MEK inhibitor, are separate, distinct compounds.

[0119] "SIFA moiety" refers to the silicon-fluoride acceptor moiety, which is contained in the covalent bond between silicon and fluorine atoms and optionally... 18 F mark.

[0120] “Chelation groups” include, in particular: (i) macrocyclic structures having 8 to 20 ring atoms, wherein 2 or more ring atoms are heteroatoms selected from oxygen and nitrogen atoms; (ii) acyclic, open-chain chelate structures having 8 to 20 main chain atoms, wherein 2 or more main chain atoms are heteroatoms selected from oxygen and nitrogen atoms; and (iii) branched chelate structures containing quaternary carbon atoms.

[0121] The term "treatment" in connection with the use of the combinations, kits, and medicines described herein is used to describe any form of intervention in which a product is administered to a subject who has, is at risk of having, or is potentially at risk of having the said disease or condition. Therefore, the term "treatment" encompasses both preventative (avoidant) treatment and curative treatment in which measurable or detectable symptoms of the disease or condition are observed.

[0122] The term "therapeuticly effective amount" (e.g., in relation to a treatment of a disease or symptom) refers to the amount of each component selected from PSMA-binding compounds and MEK inhibitors that effectively produce the desired therapeutic effect. For example, if the symptom is pain, the therapeutically effective amount is the amount sufficient to provide the desired level of pain relief. The desired level of pain relief can be, for example, complete elimination of pain or reduction of the severity of pain.

[0123] Chemical terms such as “alkyl,” “hydrocarbon,” “aromatic,” “phenyl,” “chelate” (chelate, chelate), and “cation” are used in their conventional sense (e.g., as defined in the IUPAC Gold Book) unless otherwise stated. “Optionally substituted” for any group means that the group may be substituted by one or more substituents, which may be the same or different, if desired.

[0124] For any of the compounds having a chiral center, the invention extends to all optical isomers of such compounds, whether in racemic or resolved enantiomer form. The invention described herein relates to all crystal forms, solvates, and hydrates of any of the disclosed compounds, whether or not they are prepared as such. For any of the compounds disclosed herein having an acidic or basic center (such as a carboxylic acid ester or amino group), all salt forms of the compounds are included herein. In the case of pharmaceutical use, salts should be considered pharmaceutically acceptable salts.

[0125] Salts that may be mentioned, or pharmaceutically acceptable salts, include acid addition salts and base addition salts. Such salts can be formed by conventional methods, such as by reacting the compound in its free acid or free base form with one or more equivalents of a suitable acid or base, optionally in a solvent or in a medium in which the salt is insoluble, followed by removal of the solvent or medium using standard techniques (e.g., under vacuum, by freeze-drying, or by filtration). Salts can also be prepared by exchanging one counter ion of the compound in its salt form with another counter ion, for example using a suitable ion exchange resin.

[0126] Examples of pharmaceutically acceptable salts include acid addition salts derived from inorganic and organic acids, as well as salts derived from metals such as sodium, magnesium, potassium, and calcium. Examples of acid addition salts include those formed with the following acids: acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, arylsulfonic acids (e.g., benzenesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, and p-toluenesulfonic acid), ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzoic acid, 4-acetaminobenzoic acid, butyric acid, (+)camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, decanoic acid, hexanoic acid, octanoic acid, cinnamic acid, citric acid, cyclohexane, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactopyric acid, gentian acid, glucoheponic acid, gluconic acid (e.g., D-gluconic acid), glucuronic acid (e.g., D-glucuronic acid), glutamic acid (e.g., L-glutamic acid), α-oxoglutarate, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxyethylsulfonic acid, lactic acid (e.g., (+)-L-lactic acid and (+)-DL-lactic acid), lactobionic acid, maleic acid, malic acid (e.g., (-)-L-malic acid), malonic acid, (±)-DL-mandelic acid, metaphosphoric acid, methanesulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, dihydroxynaphthoic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, tartaric acid (e.g., (+)-L-tartaric acid), thiocyanate, undecenoic acid, and valeric acid.

[0127] This also includes any solvates of the compound and its salts. Preferred solvates are those formed by incorporating molecules of a non-toxic, pharmaceutically acceptable solvent (hereinafter referred to as a solvating solvent) into the solid-state structure (e.g., crystal structure) of the compound of the invention. Examples of such solvents include water, alcohols (e.g., ethanol, isopropanol, and butanol), and dimethyl sulfoxide. Solvates can be prepared by recrystallizing the compound of the invention with a solvent or solvent mixture containing a solvating solvent. Whether a solvate has been formed in any given case can be determined by analyzing the crystals of the compound using well-known and standard techniques such as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and X-ray crystallography.

[0128] Solvates can be stoichiometric or non-stoichiometric. Specific solvates can be hydrates, and examples of hydrates include hemihydrates, monohydrates, and dihydrates. For a more detailed discussion of solvates and the methods used to prepare and characterize them, see Bryn et al., Solid-State Chemistry of Drugs, 2nd ed., published by SSCI, Inc. of West Lafayette, IN, USA, 1999, ISBN 0-967-06710-3.

[0129] In the context of this invention, the term "pharmaceutical composition" refers to a composition comprising an active agent and additionally comprising one or more pharmaceutically acceptable carriers. The composition may also contain ingredients selected from, for example, diluents, adjuvants, excipients, solvents, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatizers, antibacterial agents, antifungal agents, lubricants, and dispersants, depending on the manner of administration and the nature of the dosage form. The composition may take the form of, for example, tablets, sugar-coated pills, powders, elixirs, syrups, liquid formulations (including suspensions), sprays, inhalers, tablets, lozenges, emulsions, solutions, capsules, granules, capsules, and suppositories, as well as liquid formulations for injection (including liposome formulations).

[0130] The compounds of this invention may contain one or more isotopic substitutions, and references to a particular element include all isotopes of that element within their scope. For example, references to hydrogen include... 1 H, 2 H (D) and 3 H(T). Similarly, references to carbon and oxygen within their scope include, respectively, 12 C 13 C and 14 C and 16 O and 18O. Similarly, unless otherwise stated, references to lutetium include, within their scope, all known isotopes of lutetium, including, for example... 173 Lu、 174 Lu、 175 Lu、 176 Lu and 177 Lu. In a similar manner, references to a particular functional group also include isotopic variants within their scope, unless the context otherwise requires. For example, references to alkyl (e.g., ethyl) or alkoxy (e.g., methoxy) also cover variants in which one or more hydrogen atoms in the group are in deuterium or tritium isotopes, such as ethyl (all-deuterated ethyl) where all five hydrogen atoms are in deuterium isotopes or methoxy (trideuterated methoxy) where all three hydrogen atoms are in deuterium isotopes. Isotopes can be radioactive or non-radioactive.

[0131] The therapeutic dose can vary depending on the patient's needs, the severity of the condition being treated, and the compound used. Determining an appropriate dose for a specific situation is within the scope of the art. The effective dose of the compound will naturally vary depending on the nature of the severity of the condition being treated and the specific compound and its route of administration. Selecting an appropriate dose is within the capabilities of a person skilled in the art and does not require excessive experimentation. Typically, the daily dose can be from about 10 μg to about 30 mg / kg of human and non-human animal body weight, preferably from about 50 μg to about 30 mg / kg of human and non-human animal body weight, for example from about 50 μg to about 10 mg / kg of human and non-human animal body weight, for example from about 100 μg to about 30 mg / kg of human and non-human animal body weight, for example from about 100 μg to about 10 mg / kg of human and non-human animal body weight, and most preferably from about 100 μg to about 1 mg / kg of human and non-human animal body weight.

[0132] pharmaceutical preparations Although the active compounds of the combinations, kits and pharmaceuticals described herein can be administered individually, they are preferably presented as pharmaceutical compositions (e.g., formulations).

[0133] Therefore, in another embodiment of the invention, a combination is provided in which at least one PSMA-binding compound and a MEK inhibitor compound are presented as a pharmaceutical composition, each comprising at least one pharmaceutically acceptable excipient.

[0134] The pharmaceutical composition can be administered in any manner suitable for achieving the desired therapeutic effect. Administration can be performed in various ways, such as via enteral, parenteral, oral, intravenous, intraperitoneal, subcutaneous, intramuscular, local, intradermal, intranasal, or intrabronchial administration.

[0135] PSMA-binding compounds can be presented in parenteral formulations. PSMA-binding compounds can also be presented in intravenous formulations. PSMA-binding compounds can be administered via intravenous (IV) injection. Administration can be performed by injection and / or delivery, for example, to a specific site on the patient's body. The composition can also be administered directly to the target site, for example, via biological ballistic delivery to external or internal target sites, such as the pancreas or brain.

[0136] MEK inhibitor compounds can be presented in the form of enteral formulations. MEK inhibitor compounds can be presented in the form of tablet compositions. MEK inhibitor compounds can be presented in the form of capsule compositions. MEK inhibitors can be administered orally (PO).

[0137] Pharmaceutically acceptable excipients may be selected from, for example, carriers (e.g., solid, liquid, or semi-solid carriers), adjuvants, diluents (e.g., solid diluents, such as fillers or extenders; and liquid diluents, such as solvents and co-solvents), granulating agents, binders, flow aids, coating agents, release control agents (e.g., release-blocking or delaying polymers or waxes), adhesives, disintegrants, buffers, lubricants, preservatives, antifungal and antibacterial agents, antioxidants, buffers, tension modifiers, thickeners, flavoring agents, sweeteners, pigments, plasticizers, taste maskers, stabilizers, or any other excipients conventionally used in pharmaceutical compositions.

[0138] As used herein, "pharmaceutically acceptable" means, to a reasonable extent of medical judgment, a compound, material, composition, and / or dosage form that is suitable for contact with the tissues of a subject (e.g., a human subject) without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that provides a reasonable benefit / risk ratio. Each excipient must also be "acceptable" in terms of compatibility with other components of the formulation.

[0139] Pharmaceutical compositions containing compounds, kits, and drugs described herein can be formulated using known techniques, see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA. Pharmaceutical compositions can be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ocular, ocular, rectal, vaginal, or transdermal administration.

[0140] Suitable dosage forms for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), capsules, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, rice paper capsules, or patches such as buccal patches.

[0141] Tablet compositions may contain a unit dose of an active compound and an inert diluent or carrier, such as sugars or sugar alcohols, like lactose, sucrose, sorbitol, or mannitol; and / or non-sugar-derived diluents, such as sodium carbonate, calcium phosphate, calcium carbonate, or cellulose or its derivatives, such as microcrystalline cellulose (MCC), methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, and starch, such as corn starch. Tablets may also contain such standard ingredients, such as binders and granulators (e.g., polyvinylpyrrolidone), disintegrants (e.g., swellable cross-linked polymers, such as cross-linked carboxymethyl cellulose), lubricants (e.g., stearates), preservatives (e.g., parabens), antioxidants (e.g., BHT), buffers (e.g., phosphate or citrate buffers), and effervescent agents (e.g., citrate / bicarbonate mixtures). Such excipients are well known and do not need to be discussed in detail herein.

[0142] Tablets can be designed to release the drug upon contact with gastric juices (immediate-release tablets) or to release the drug in a controlled manner over a prolonged period of time or in a specific region of the gastrointestinal tract (controlled-release tablets).

[0143] Pharmaceutical compositions typically comprise from about 1% (w / w) to about 95% (w / w), preferably % (w / w), of an active ingredient and from 99% (w / w) to 5% (w / w) of a pharmaceutically acceptable excipient (e.g., as defined above) or a combination of such excipients. Preferably, the composition comprises from about 20% (w / w) to about 90% (w / w) of an active ingredient and from 80% (w / w) to 10% of a pharmaceutical excipient or a combination of excipients. Pharmaceutical compositions according to the invention may be in, for example, unit dosage forms, such as ampoules, vials, suppositories, pre-filled syringes, sugar-coated pills, powders, tablets, or capsules.

[0144] Tablets and capsules may contain, for example, 0-20% disintegrants, 0-5% lubricants, 0-5% flow aids, and / or 0-99% (w / w) fillers or expanders (depending on the drug dosage). They may also contain 0-10% (w / w) polymer binders, 0-5% (w / w) antioxidants, and 0-5% (w / w) pigments. In addition, sustained-release tablets typically contain 0-99% (w / w) controlled-release (e.g., delayed-release) polymers (depending on the dosage). Film coatings of tablets or capsules typically contain 0-10% (w / w) polymers, 0-3% (w / w) pigments, and / or 0-2% (w / w) plasticizers.

[0145] Parenteral preparations typically contain 0-20% (w / w) buffer, 0-50% (w / w) co-solvent, and / or 0-99% (w / w) water for injection (WFI) (depending on the dosage and whether it is lyophilized). Preparations for intramuscular reservoirs may also contain 0-99% (w / w) oil.

[0146] The drug formulation can be presented to the patient in the form of a "patient package," which contains the entire course of treatment in a single package (usually a blister pack).

[0147] These pharmaceutical compositions can be administered to subjects at appropriate doses. The active compound is administered to a patient in need (e.g., a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect (effective dose). The precise dosage of each compound can be determined by the attending physician according to standard procedures. As is well known in the medical field, the dosage for any given patient depends on many factors, including the patient's body size, body surface area, age, the specific compound to be administered, sex, time and route of administration, general health condition, and other medications administered concurrently. The active pharmaceutical ingredient can be present in a therapeutically effective dose, which can range from 0.1 ng to 10 mg / kg body weight per dose; however, doses below or above this exemplary range are also contemplated, particularly taking into account the factors mentioned above.

[0148] Example The present invention will now be described with reference to the following embodiments, but the invention is not limited thereto.

[0149] Preparation of the compounds of the present invention PSMA-binding compounds can be prepared according to methods known in the art, including those described in WO2019 / 020831, WO2020 / 157177, WO2020 / 157184, WO2022 / 144467, WO2022 / 144463 and WO2022 / 171901.

[0150] General information Analytical and preparative high-performance liquid chromatography (HPLC) was performed using a Shimadzu gradient system (Neufaen, Germany) equipped with an SPD-20A UV / Vis detector. Analytical columns (MultoKrom 100C18, 150 × 4.6 mm, 5 μm), radioanalytical columns (Multospher 100RP18, 125 × 4.6 mm, 5 μm), and preparative columns (MultoKrom 100C18, 250 × 20 mm, 5 μm) were purchased from CS Chromatographie Service (Langweer, Germany). The eluents used for all HPLC operations were water (solvent A) and acetonitrile (solvent B) containing 2 vol% water, both containing 0.1 vol% trifluoroacetic acid (TFA). Radioactivity was detected using a HERM LB 500NaI detector (Berthold Technologies, Bad Werder Bate, Germany). Radioactive thin-layer chromatography (TLC) was performed using a Scan-RAM detector (LabLogic Systems, Sheffield, UK). L Electrospray ionization-mass spectrometry was obtained on CMS (Advion, Harlow, UK).

[0151] rhPSMA-10.1 rhPSMA-10.1 in the form of a free chelating agent was synthesized according to the methods described in WO2020 / 157184 and WO2020 / 157177. Briefly, in DMF, the tert-butyl-protected chelating agent DOTA (…) was… t Bu)3 is attached to the free N - End, duration 2 hours. Deprotection of the resin from cleavage and acid-labile protecting groups was carried out in TFA for 6 hours. After RP-HPLC purification, a colorless solid rhPSMA-10.1 (18%) was obtained. RP-HPLC (10-70% B, within 15 min): t R = 9.9 min, K' = 3.95. Monoisotopic mass (C 60 H 95 FN 12 O 23 Calculated value of Si: 1398.6; Measured value: m / z = 1399.6 [M+H] + 700.6 [M+2H] 2+ .

[0152] A 2 mM solution of rhPSMA-10.1 (1.0 equivalent) in DMSO was heated to 95 °C and maintained for 30 minutes with a 20 mM aqueous solution of LuCl3 (2.5 equivalent) to prepare [the product]. nat LurhPSMA-10.1. After cooling, confirmation was performed using RP-HPLC and MS. nat Formation of Lu-chelates.

[0153] nat Lu-rhPSMA-10.1: RP-HPLC (10-70% B, within 15 min): t R = 9.9 min, K' = 3.95. Monoisotopic mass (C 60 H 92 FLuN 12 O 23 Calculated value of Si: 1570.6; Measured value: m / z = 1572.2 [M+H] + 786.6 [M+2H] 2+ .

[0154] 177 Lu-rhPSMA-10.1 Radiolabeling was performed in ~40 μL of 0.045 sodium acetate (NaOAc) buffer (Sigma Aldrich) with a molar activity (MA) of ~25 MBq / nmol, with each reaction scale being 2 nmol rhPSMA. The precursor (…) was added from frozen aliquots of 1 mM DMSO stock solution… nat Lu-rhPSMA-10.1), and in buffer and 177 Lu was heated at 50°C for 30 minutes. Instantaneous thin-layer chromatography (iTLC) was performed on glass microfiber chromatography paper (Agilent Technologies) using citrate (0.1M, pH 5) as the developing solvent, and the bands were analyzed using a Bioscan AR-2000 radio-TLC scanner (Eckert & Ziegler). Analysis was based on the unbound bands at the solvent front. 177 Compared to Lu activity, the activity of radiolabeled compounds retained at baseline was calculated for radiochemical yield (RCY) and radiochemical purity (RCP), and both were >98% for all radiolabels.

[0155] MEK inhibitors Cobimetinib is commercially available (MedChemExpress), but can also be prepared using methods known in the art.

[0156] Bioactivity Example A - In vitro study At different cobimetinib concentrations and different 177 At a dose of Lu-rhPSMA-10.1, cobimetinib and 177 The therapeutic effects of the Lu-rhPSMA-10.1 combination. In a series of... 177 Evaluation of cobimetinib IC50 at Lu-rhPSMA-10.1 concentration 50 Zero interaction power (ZIP) analysis and multidimensional synergy (MuSyc) analysis of the combinatorial system were performed.

[0157] The 22Rv1 human prostate adenocarcinoma cell line (ATCC; CRL-2505) was used. Cells were maintained in complete Roswell Park Memorial Institute (RPMI) medium (10% fetal bovine serum [FBS], L-glutamine, penicillin / streptomycin) and used for experiments after passages of 10–20.

[0158] Based on the above conditions 177 Radiolabeling was performed using Lu-rhPSMA-10.1. The suspension (1.67 × 10⁻⁶) was used for radiolabeling. 6 22Rv1 cells were prepared in a solution of cells / mL and then... 177 Lu-rhPSMA-10.1 was incubated at 37°C for 2 hours with gentle stirring until a final volume of 3.2 mL was obtained. Only cell solutions from the same cell suspension batch (3.2 mL, 1.67 × 10⁻⁶) were used. 6 A control was prepared (cells / mL).

[0159] A series of dilutions of cobimetinib were prepared using a 3-fold dilution method in 180 μL of complete RPMI medium, starting at a concentration of 8 μM. For cobimetinib alone and in combination... 177 Lu-rhPSMA-10.1 treatment was used to prepare a series of dilutions, which were then spread in quadruplicate at each concentration (20 μL / well) in 96-well plates (Corning® 96-well clear flat-bottom polystyrene TC-treated microplates). Multiple dosages were evaluated. 177 Lu-rhPSMA-10.1 (0, 5, 10, 15, 20, 25 MBq / mL).

[0160] The cell suspension was diluted with culture medium and dispensed into wells pretreated with cobimetinib solution, with a final well volume of 200 μL. 177Lu-rhPSMA-10.1 treated cells, which represents 1600 cells / well; for plates with only cobimetinib, this represents 800 cells / well to compensate for the 15 MBq / mL concentration alone. 177 The expected reduction in colony formation survival caused by Lu-rhPSMA-10.1 treatment was investigated. These plates were incubated at 37°C and 5% CO2 for 10 days, followed by treatment with hard phosphate-buffered saline (PBS; Ca2+). 2+ and Mg 2+ Wash the plates and stain them with a 1:4 methanol:ethanol solution of 0.05 w / w% crystal violet for at least 1 hour. Wash the stained plates with distilled water and air dry. Scan and analyze colony counts using a Celigo imaging cell counter.

[0161] Survival fractions were calculated as the number of colonies formed divided by the number of cells seeded, and normalized to the control (DMSO 0.5% (v / v)). This was achieved by normalizing to single-drug treatments (without...). 177 Lu-rhPSMA-10.1) was used to further adjust the survival score. Figure 1 The figures show the effects of different cobimetinib concentrations and different... 177 Survival fraction data at Lu-rhPSMA-10.1 dose.

[0162] Figure 1 The data provided in the paper proves that it contains cobimetinib and 177 Synergistic therapeutic efficacy of Lu-rhPSMA-10.1 combination in vitro (22Rv1 prostate cancer cell line).

[0163] For comparative purposes, the experimental procedures described above were followed to evaluate the effects of AZD0156, belzocetinib, and everolimus on their respective effects on... 177 The therapeutic effects of Lu-rhPSMA-10.1 combinations were evaluated using different optimized starting concentrations: cobimetinib (8 µM), AZD0156 (3 µM), belzocetinib (750 nM), and everolimus (100 nM).

[0164] Collaborative Analysis Two collaborative analysis platforms known to those skilled in the art were used to analyze in vitro data: SynergyFinder (https: / / synergyfinder.fimm.fi / ) and the combined multidimensional synergy platform (MuSyC; https: / / musyc.lolab.xyz / about ).

[0165] SynergyFinder is a standalone web application for interactive analysis and visualization of multidose combination response data for multiple drugs (two or more drugs) (Ianevski A, Giri AK, Aittokallio T). Nucleic Acids Res. 2022 Jul 5;50(W1):W739-W743). SynergyFinder quantifies the degree of synergistic or antagonistic effects of combinations by comparing observed drug combination responses with expected responses calculated using a reference model assuming no interactions between drugs (selected from Zero Interaction Power (ZIP), Bliss Independence, Loewe Additivity, or Highest Single Agent (HSA)).

[0166] ZIP reference models capture drug interactions by comparing changes in the potency (effect at a given dose level) of dose-response curves between individual drugs and their combinations (Yadav B, Wennerberg K, Aittokallio T, Tang J). Comput Struct Biotechnol J. 2015 Sep 25;13:504-13.doi: 10.1016 / j.csbj.2015.09.001). The ZIP model combines the advantages of Loewe's additivity and Bliss's independence models, aiming to systematically evaluate various types of drug interaction patterns that may occur in high-throughput drug combination screening. ZIP assumes that two non-interacting drugs are expected to cause minimal changes in their dose-response curves. Positive and negative values ​​represent the deviation between the measured and expected responses, thus indicating synergistic and antagonistic effects, respectively.

[0167] ZIP synergy score can be interpreted as the average additional response due to drug interactions; for example, a synergy score of 10 corresponds to a response exceeding the expected 10%, such as 10% more cell inhibition (Yadav B, Wennerberg K, Aittokallio T, Tang J). Comput Struct Biotechnol J. 2015 Sep 25;13:504-13.doi: 10.1016 / j.csbj.2015.09.001). >5% was considered a high ZIP synergistic score. For ZIP score analysis, the survival score and corresponding cobimetinib (or other appropriate contrast agent) and 177 The Lu-rhPSMA-10.1 dose was uploaded to SynergyFinder and a ZIP score was calculated.

[0168] The second synergistic platform, MuSyC, can be used to determine whether the observed synergistic effect is due to the enhanced potency or efficacy of a single agent (Meyer CT et al.). Cell Syst. 2019 Feb 27;8(2):97-108). MuSyC is based on a two-dimensional (2D) extension of the Hill equation derived from mass action kinetics. The parameter α quantifies how the effective dose of one drug changes due to the presence of another drug, and vice versa. In the case of synergistic potency (indicated by Logα > 0, where α can correspond to either drug, e.g. 177 Lu-rhPSMA-10.1 or cobitinib), EC 50 The effect is reduced due to the addition of another second drug, which corresponds to an increase in potency.

[0169] To perform MuSyC analysis, the mean survival score, the corresponding cobimetinib (or other appropriate contrast agent), and 177 The Lu-rhPSMA-10.1 dose and 95% confidence interval (CI=95%) (calculated using GraphPad Prism) were uploaded to MuSyC, and the Logα score for synergistic efficacy was calculated.

[0170] Based on ZIP analysis, cobimetinib and 177 The combination of Lu-rhPSMA-10.1 exhibited overall synergistic interactions (e.g., synergistic enhancement of therapeutic efficacy) across different active concentration ranges (Table 1). Figure 2 Based on MuSyc analysis, the observed synergistic effect appears to be due to the combination of cobibitinib and... 177 Lu-rhPSMA-10.1 enhances the efficacy of both.

[0171] Table 1 - ZIP Synergy Score and MuSyc Synergy Effectiveness Score Example B - In vivo study Prostate cancer xenotransplantation model Based on tumor volume and survival in a 22Rv1 tumor cell-derived prostate cancer model (Sigma Aldrich) established in 6-week-old male NMRI nude mice (Janvier, France), the tumor volume and survival were assessed. 177 The efficacy of the combination of Lu-rhPSMA-10.1 and cobimetinib. Prior to inoculation, 22Rv1 cells were maintained in complete RPMI medium (10% fetal bovine serum [FBS], L-glutamine, penicillin / streptomycin).

[0172] program Anesthetize the animals and place them in a prone position on a sterile barrier. Place 3 × 10 6 100 μL of 1:1 PBS / Matrigel per cell was subcutaneously seeded into the right flank. Individual animal identification was ensured using a microarray. Tumors with a volume of 100-200 mm were targeted. 3 Animals were included in the study. Intravenous (IV) and oral (PO) administration were performed in unanesthetized animals. The injection site was the lateral caudal vein.

[0173] As detailed in Table 2, cobimetinib is administered once daily for 21 days (QD×21). 177 Lu-rhPSMA-10.1 is administered as a single dose. For patients receiving cobimetinib and 177 The Lu-rhPSMA-10.1 group, 177 Lu-rhPSMA-10.1 was administered before the first dose of cobimetinib on day 1. The groups included in this study are listed in Table 2.

[0174] Tumor growth was monitored starting 5 days after inoculation. Tumor size was measured twice weekly, on the day of randomization, using calipers. Tumor volume was estimated using the following formula: 0.52 (length × width) 2 Animal weight was also monitored. If the weight loss exceeded 20% relative to the weight on day 1 of the study (where day 0 is the start of treatment), the animal was euthanized as a humane endpoint.

[0175] Data presentation and statistical analysis were performed in GraphPad Prism. The effect of treatment on tumor volume was evaluated from study day 1 to the study end date (which was predetermined), or until three or more animals remained alive in each group. Tumor volume was continuously tracked until three animals remained in each group. Survival analysis was performed until the study end date or when animals reached the endpoint (tumor volume >1500 mm). 2 The analysis and summary are shown in Table 3.

[0176] Table 2: Group Overview Table 3: Statistical Analysis of In Vivo Efficacy Studies Tumor volume, survival rate, and relative body weight data are presented in Figures 3 to 5 In the middle. Compared with the untreated control group (Group A), the combination treatment group ( 177 The Lu-rhPSMA-10.1 + cobimetinib-D group showed the strongest effect on mean tumor volume, demonstrating significant tumor growth inhibition from day 13 to day 30 of the study (p<0.01, two-way ANOVA, Tukey's multiple comparison test). Compared with only...177 Compared to Lu-rhPSMA-10.1 (Group C), the combined treatment group ( 177 The Lu-rhPSMA-10.1+cobitinib-D group significantly suppressed the mean tumor volume from day 17 to day 30 of the study (p<0.001, two-way ANOVA, Tukey's multiple comparison test).

[0177] For the untreated control group (Group A), the median survival was 23 days; for the cobimetinib group (Group B), the median survival was 39 days; for 177 Lu-rhPSMA-10.1 (Group C), median survival was 36 days; for 177 The combination of Lu-rhPSMA-10.1 and cobimetinib (group D) had a median survival of 49 days. Compared with the untreated control group (p=0.001) and 177 Compared with the Lu-rhPSMA-10.1 group (p=0.002), the combination therapy group (Group D) showed a significant improvement in survival according to the log-rank Mantel-Cox survival test.

[0178] Some transient weight loss was observed in both groups (Group B and Group D) treated with cobimetinib. However, the mean relative weight loss did not exceed 10%, indicating no significant compound-related toxicity.

[0179] Data shows that, compared to any single drug, 177 The combination of Lu-rhPSMA-10.1 and cobitinib (a MEK inhibitor) enhanced in vivo therapeutic efficacy (22Rv1 prostate cancer xenograft model).

[0180] Examples A and B together demonstrate that, compared to the therapeutic efficacy expected when considering the efficacy of each drug individually, 177 The combination of Lu-rhPSMA-10.1 and cobitinib (a MEK inhibitor) provided significantly enhanced therapeutic efficacy in both in vitro and in vivo prostate cancer models. Attached Figure Description

[0181] Figure 1 Example A: Combined screening data (at different cobimetinib concentrations and different...) 177 Survival fraction at Lu-rhPSMA-10.1 dose). Data are presented as mean ± SD, N=4 / group.

[0182] Figure 2 ZIP synergistic analysis of data from Example A (at different cobimetinib concentrations and different...) 177 Median percentage of inhibition ± SD and ZIP combined score at Lu-rhPSMA-10.1 dose.

[0183] Figure 3 Tumor volume data from Example B (during application) 177 Lu-rhPSMA-10.1 (30 MBq, single dose), cobimetinib (0.25 mg, QD×21) or 177 Lu-rhPSMA-10.1 (30 MBq, single dose) plus cobimetinib (0.25 mg, QD×21) was administered. Data are presented as mean ± SEM, N=7-8 / group.

[0184] Figure 4 Survival percentage data for Example B (at the time of application) 177 Lu-rhPSMA-10.1 (30 MBq, single dose), cobimetinib (0.25 mg, QD×21) or 177 Lu-rhPSMA-10.1 (30 MBq, single dose) plus cobimetinib (0.25 mg, QD×21) was administered. Data are presented as mean ± SEM, N=7-8 / group.

[0185] Figure 5 Relative body weight data from Example B (during application) 177 Lu-rhPSMA-10.1 (30 MBq, single dose), cobimetinib (0.25 mg, QD×21) or 177 Lu-rhPSMA-10.1 (30 MBq, single dose) plus cobimetinib (0.25 mg, QD×21) was normalized to day 1 of treatment. Data are presented as mean ± SEM, N=7–8 / group.

Claims

1. A combination of compounds comprising (i) a PSMA-binding compound and (ii) a MEK inhibitor, wherein the PSMA-binding compound comprises: (a) One or more ligands capable of binding PSMA; and (b) One or more chelating groups, wherein the one or more chelating groups contain chelated radioactive metal cations.

2. The combination according to claim 1, wherein the PSMA-binding compound (i) further comprises: (c) The silicon-fluoride acceptor (SIFA) portion, which consists of a covalent bond between silicon and fluorine atoms.

3. The combination according to any one of claims 1 or 2, wherein one or more ligands of said PSMA-binding compound (i) capable of binding PSMA comprise a structure represented by formula (1): (1)。 4. The combination according to any one of claims 1 to 3, wherein the one or more chelating groups of (b) of the PSMA-binding compound (i) comprise residues of a chelating agent selected from 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA), α-(2-carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTAGA), and 1,4,7-triazacyclononane-1,4,7-tris[methylene(2-carboxyethyl)phosphonic acid] (TRAP).

5. The combination according to any one of claims 2 to 4, wherein the silicon-fluoride acceptor (SIFA) portion of (c) of the PSMA-binding compound (i) comprises a structure represented by formula (2): (2)。 6. The combination according to claim 1, wherein the PSMA-binding compound (i) is selected from: ； ； Or a pharmaceutically acceptable salt thereof, wherein M 3+ It is a chelated radioactive metal cation.

7. The combination according to claim 1, wherein the PSMA-binding compound (i) is selected from: ； ； and its pharmaceutically acceptable salts, of which M 3+ It is a chelated radioactive metal cation.

8. The combination according to any one of claims 1 to 7, wherein the chelated radioactive metal cation is selected from Sc 3 + Cu 3+ Ga 3+ Y 3+ In 3+ 、Tb 3+ Ho 3+ Lu 3+ Re 3+ Pb 3+ Bi 3+ Ac 3+ Er 3+ and Th 3+ .

9. The combination according to claim 8, wherein the chelated radioactive metal cation is selected from... 64 Cu 3+ , 67 Cu 3+ , 149 Tb 3+ , 152 Tb 3+ , 155 Tb 3+ , 161 Tb 3+ , 225 Ac 3+ , 68 Ga 3+ and 177 Lu 3+ .

10. The combination according to claim 9, wherein the chelated radioactive metal cation is 177 Lu 3+ .

11. The combination according to claim 9, wherein the chelated radioactive metal cation is 225 Ac 3+ .

12. The combination according to claim 1, wherein the PSMA-binding compound (i) is: ； Or its pharmaceutically acceptable salt.

13. The combination of any one of claims 1 to 12, wherein the MEK inhibitor is selected from: ； ； ； ； Or its pharmaceutically acceptable salt.

14. The combination according to claim 13, wherein the MEK inhibitor is: ； Or its pharmaceutically acceptable salt.

15. The combination according to claim 1, wherein the PSMA-binding compound (i) is: ； Or its pharmaceutically acceptable salt; And the MEK inhibitor is: ； Or its pharmaceutically acceptable salt.

16. A medicament comprising the combination according to any one of claims 1 to 15.

17. A kit comprising (i) a PSMA-binding compound as defined in any one of claims 1 to 15 and (ii) a MEK inhibitor as defined in any one of claims 1 to 15.

18. The combination, medicament or kit according to any one of claims 1 to 17, for the treatment of cancer.

19. The combination, drug, or kit according to claim 18, for treating cancer, wherein the cancer is prostate cancer, salivary gland cancer, thyroid cancer, hepatocellular carcinoma, glioblastoma, glioma, testicular cancer, breast cancer, lung cancer, colorectal cancer, or renal cell carcinoma.

20. The combination, drug, or kit according to claim 19, for the treatment of prostate cancer.

21. The combination, medicament, or kit according to any one of claims 18 to 20, wherein the therapeutic application of the combination of the compound comprising the PSMA-binding compound as defined in any one of claims 1 to 15 and the MEK inhibitor as defined in any one of claims 1 to 15 provides a synergistic enhancement of therapeutic efficacy in cancer treatment, and appropriately in prostate cancer treatment, compared to the expected cumulative therapeutic efficacy that would be produced by combining the compounds when considering the therapeutic efficacy of each compound (i) and (ii) individually.

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