Drug combinations for treating triple-negative breast cancer

Abstract

A combination drug for treating triple-negative breast cancer. A proteolytic agent based on a dosamine-based E3 ligase ligand targeting the androgen receptor can effectively prevent and / or treat triple-negative breast cancer (including androgen receptor-positive triple-negative breast cancer). The combination of an androgen receptor proteolytic agent based on a dosamine-based E3 ligase ligand with a target drug (including a PI3Kα inhibitor, a PARP inhibitor), an immunotherapy drug or a chemotherapy drug can effectively prevent and / or treat triple-negative breast cancer.

Description

[Technical field]

[0001] The present invention relates to the field of medicine, specifically to a drug combination for treating triple-negative breast cancer. [Background technology]

[0002] Breast cancer is the most common malignant tumor in women worldwide, and its incidence and mortality are the first among female tumors, which poses a serious threat and risk to women's mental and physical health. Breast cancer types have significantly different biological characteristics and clinical symptoms, and currently, in clinical practice, breast cancer is classified into four molecular subtypes based on the detection of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2) mainly by immunohistochemistry: luminal A type (ER positive or PR positive, HER-2 negative, Ki67 low expression), luminal B type (ER positive or PR positive, HER-2 positive), HER-2 overexpression type (ER, PR negative, HER-2 positive, Ki67 mostly high expression) and basal-like type (ER, PR, HER-2 negative). Triple negative breast cancer (TNBC) is the most malignant subtype of breast cancer and is characterized by being negative for ER, PR and HER-2. It is also known to have a high recurrence rate, early metastasis rate, aggressiveness and poor prognosis.

[0003] At present, chemotherapy is one of the main methods for treating breast cancer. Cyclophosphamide, doxorubicin, and 5-fluorouracil (5-FU) have long been recognized as the first-choice chemotherapy drugs in the treatment of advanced breast cancer, but with the emergence of drugs such as paclitaxel, more and more clinicians have come to believe that paclitaxel and cisplatin can also be the first choice of chemotherapy. However, the therapeutic effects of these chemotherapy drugs still have room for improvement.

[0004] The androgen receptor (AR) belongs to the family of nuclear receptors and is a ligand-dependent transcription factor. Abnormal regulation of the AR signaling pathway plays an important role in the development and progression of prostate cancer, and studies have shown that castration-resistant prostate cancer (CRPC) remains dependent on the action of AR. Proteolysis-inducing chimeras (PROTACs) have attracted widespread attention as small molecules that can induce the degradation of target proteins. PROTACs, which are bifunctional molecules, contain small molecule compounds that can bind to a protein of interest (POI), a linker is introduced at the appropriate position, and then conjugate with a small molecule compound that can bind to a ubiquitin protease. The resulting small molecule probe can simultaneously bind to the target protein and the ubiquitin protease, thereby promoting the ubiquitination of the target protein, and the multiply ubiquitinated protein is recognized and degraded by the proteasome. By using the PROTACs strategy to prepare proteolysis-inducing chimeras (AR PROTACs) that can target and recognize / bind to the androgen receptor, it is possible to control the level of androgen receptor through the intracellular ubiquitin-proteasome degradation system and induce the degradation of the androgen receptor, thereby providing therapeutic effects on androgen receptor-regulated related diseases such as prostate cancer.

[0005] However, there have been no reports to date of using proteolysis-inducing androgen receptor chimeras to treat triple-negative breast cancer. Summary of the Invention

[0006] One object of the present invention is to provide a use of an androgen receptor targeting degrader based on a dosamine-based E3 ligase ligand in the preparation of a medicament for the prevention and / or treatment of triple-negative breast cancer.

[0007] Another object of the present invention is to provide a use of an androgen receptor targeting degrader based on a dosamine-based E3 ligase ligand in combination with a targeted drug (including a PI3Kα inhibitor, a PARP inhibitor), an immunotherapy drug or a chemotherapy drug in the preparation of a drug for preventing and / or treating triple-negative breast cancer.

[0008] The present invention provides the use of an androgen receptor-targeting degrader based on a dosamine-based E3 ligase ligand in the preparation of a medicament for preventing and / or treating triple-negative breast cancer.

[0009] The present invention also provides the use of a combination of an androgen receptor-targeting degrader based on a dosamine-based E3 ligase ligand and a targeted drug in the preparation of a drug for preventing and / or treating triple-negative breast cancer.

[0010] Moreover, the targeted drug is a PI3K inhibitor.

[0011] Further, said PI3K inhibitor is a PI3Kα inhibitor.

[0012] Furthermore, the PI3K inhibitor is the following compound, or an optical isomer thereof, a tautomer thereof, a salt thereof, a prodrug thereof, a hydrate thereof, or a solvate thereof, and the compound is alpelisib, GDC-0077, TAK-117, AZD-8186, IPI-549, idelalisib, buparlisib, piralalisib, copanlisib, PX-866, paxalisib, duvelisib, umbralisib, taselisib, perifosine, buparlisib, dactolisib, CUDC-907, or voxtalisib.

[0013] Furthermore, the targeted drug is a PARP inhibitor.

[0014] Further, the PARP inhibitor is olaparib, rucaparib, talazopanib, niraparib, pamiparib or fluzoparib.

[0015] Furthermore, the targeted drug is alpelisib, and the molar ratio of the androgen receptor-targeting degrader to alpelisib is 1:27 to 3:1; Or, the targeted drug is duvelisib, and the molar ratio of the androgen receptor-targeting decomposition agent to duvelisib is 1:30 to 1:10; Or, the targeted drug is idelalisib, and the molar ratio of the androgen receptor-targeting decomposer to idelalisib is 1:270 to 1:90.

[0016] The present invention also provides the use of a combination of an androgen receptor targeting degrader based on a dosamine-based E3 ligase ligand and an immunotherapy drug in the preparation of a drug for preventing and / or treating triple-negative breast cancer.

[0017] The present invention also provides the use of a combination of an androgen receptor targeting degrader based on a dosamine-based E3 ligase ligand and a chemotherapy drug in the preparation of a medicament for preventing and / or treating triple-negative breast cancer.

[0018] Further, the chemotherapy drug is paclitaxel or 5-fluorouracil.

[0019] Furthermore, the chemotherapy drug is paclitaxel, and the molar ratio of the androgen receptor targeting degrader to paclitaxel is 20:1 to 5000:1; Or, the chemotherapy drug is 5-fluorouracil, and the molar ratio of the androgen receptor targeting degrader to 5-fluorouracil is 1.85:1 to 5.54:1.

[0020] Furthermore, the decomposition agent targeting the androgen receptor is a PROTAC bifunctional chimeric molecule as shown in formula (I), or an optical isomer thereof, a tautomer thereof, or a pharma- ceutically acceptable salt thereof. TIFF2025515917000001.tif22170

[0021] where ARB is a ligand for the androgen receptor, L is a linker, and U is a ligand for the E3 ligase.

[0022] Furthermore, U is a CRBN E3 ligase ligand and has the following structure: TIFF2025515917000002.tif23170

[0023] wherein E is an unsubstituted or substituted benzene ring, a 5-membered aromatic heterocycle, a 6-membered aromatic heterocycle, a benzoaromatic heterocycle, or an unsaturated benzoheterocycle; E X is none, halogen, oxygen, sulfur, nitrogen, carbonyl group, -(CH 2 )-and E Y is none, H, or a carbonyl group.

[0024] Furthermore, the U is a CRBN E3 ligase ligand.

[0025] Furthermore, the structure of U is selected from the following: TIFF2025515917000003.tif46170TIFF2025515917000004.tif48170TIFF2025515917000005.tif40170TIFF2025515917000006.tif53170

[0026] Further, the PROTAC bifunctional chimeric molecule is selected from ARV-110, ARV-766, HP518, AC0176, GT20029, ASN-1780, ARD-2128, ARD-2585.

[0027] Furthermore, the structure of the PROTAC bifunctional chimeric molecule is as shown in formula (II). TIFF2025515917000007.tif39170

[0028] Where X is F, Cl, Br, Me, or CF 3 is selected from Y is selected from CH or N; W is selected from O, S, and NMe; Ring A is R 1 , R 2 , R 3 and / or R 4 cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, R 1 , R 2 , R 3 , R 4 , R 5 are each independently selected from hydrogen and Me; Ring B is selected from a 5-membered aromatic heterocycle, a 6-membered aromatic ring, and a 6-membered aromatic heterocycle; G 1 , G 2 , G 3 are each independently CR 6 , N, where R 6 is selected from H, a halogen, and a hydroxy group; n1, n2, n3, n4, n5, and n6 are each independently selected from 1 or 2; M is for CR 7 R 8 where R 7 , R 8 are each independently selected from H and Me; Z is selected from H, F, Cl, Me.

[0029] Further, the structure of said PROTAC bifunctional chimeric molecule is selected from the following: TIFF2025515917000008.tif29170TIFF2025515917000009.tif62170TIFF2025515917000010.tif28170TIFF2025515917000011.tif38170TIFF2025515917000012.tif45170TIFF2025515917000013.tif39170TIFF2025515917000014.tif38170TIFF2025515917000015.tif38170TIFF2025515917000016.tif39170TIFF2025515917000017.tif38170TIFF2025515917000018.tif37170TIFF2025515917000019.tif28170TIFF2025515917000020.tif22170TIFF2025515917000021.tif41170TIFF2025515917000022.tif15170TIFF2025515917000023.tif38170TIFF2025515917000024.tif39170TIFF2025515917000025.tif41170TIFF2025515917000026.tif38170TIFF2025515917000027.tif54170TIFF2025515917000028.tif45170TIFF2025515917000029.tif54170TIFF2025515917000030.tif30170TIFF2025515917000031.tif47170TIFF2025515917000032.tif74170TIFF2025515917000033.tif47170TIFF2025515917000034.tif71170TIFF2025515917000035.tif20170TIFF2025515917000036.tif40170TIFF2025515917000037.tif65170TIFF2025515917000038.tif29170TIFF2025515917000039.tif62170TIFF2025515917000040.tif29170TIFF2025515917000041.tif46170TIFF2025515917000042.tif38170TIFF2025515917000043.tif44170TIFF2025515917000044.tif44170TIFF2025515917000045.tif47170TIFF2025515917000046.tif40170TIFF2025515917000047.tif20170TIFF2025515917000048.tif39170TIFF2025515917000049.tif37170TIFF2025515917000050.tif40170TIFF2025515917000051.tif38170TIFF2025515917000052.tif47170TIFF2025515917000053.tif44170TIFF2025515917000054.tif40170TIFF2025515917000055.tif38170TIFF2025515917000056.tif38170TIFF2025515917000057.tif38170TIFF2025515917000058.tif37170TIFF2025515917000059.tif37170TIFF2025515917000060.tif37170TIFF2025515917000061.tif41170TIFF2025515917000062.tif44170TIFF2025515917000063.tif37170TIFF2025515917000064.tif37170TIFF2025515917000065.tif44170TIFF2025515917000066.tif46170TIFF2025515917000067.tif44170TIFF2025515917000068.tif36170TIFF2025515917000069.tif38170TIFF2025515917000070.tif44170TIFF2025515917000071.tif70170TIFF2025515917000072.tif27170TIFF2025515917000073.tif53170TIFF2025515917000074.tif39170TIFF2025515917000075.tif49170TIFF2025515917000076.tif63170TIFF2025515917000077.tif50170TIFF2025515917000078.tif39170TIFF2025515917000079.tif45170TIFF2025515917000080.tif53170TIFF2025515917000081.tif53170TIFF2025515917000082.tif38170TIFF2025515917000083.tif44170TIFF2025515917000084.tif32170TIFF2025515917000085.tif49170TIFF2025515917000086.tif20170TIFF2025515917000087.tif45170TIFF2025515917000088.tif61170TIFF2025515917000089.tif38170TIFF2025515917000090.tif20170TIFF2025515917000091.tif62170TIFF2025515917000092.tif47170TIFF2025515917000093.tif53170TIFF2025515917000094.tif57170TIFF2025515917000095.tif62170TIFF2025515917000096.tif49170TIFF2025515917000097.tif38170TIFF2025515917000098.tif49170TIFF2025515917000099.tif40170TIFF2025515917000100.tif55170TIFF2025515917000101.tif55170TIFF2025515917000102.tif57170TIFF2025515917000103.tif49170TIFF2025515917000104.tif39170TIFF2025515917000105.tif20170TIFF2025515917000106.tif54170TIFF2025515917000107.tif62170TIFF2025515917000108.tif49170TIFF2025515917000109.tif62170TIFF2025515917000110.tif56170TIFF2025515917000111.tif55170 TIFF2025515917000112.tif57170TIFF2025515917000113.tif55170TIFF2025 515917000114.tif49170TIFF2025515917000115.tif45170TIFF202551591700 0116.tif57170TIFF2025515917000117.tif54170TIFF2025515917000118.tif1 9170TIFF2025515917000119.tif56170TIFF2025515917000120.tif58170TIFF 2025515917000121.tif70170TIFF2025515917000122.tif56170TIFF202551591 7000123.tif30170TIFF2025515917000124.tif39170TIFF2025515917000125. tif56170TIFF2025515917000126.tif54170TIFF2025515917000127.tif54170.

[0030] Furthermore, the triple-negative breast cancer is androgen receptor-positive triple-negative breast cancer.

[0031] The present invention is the first to discover that an androgen receptor-targeting proteolytic agent can effectively prevent and / or treat triple-negative breast cancer (including androgen receptor-positive triple-negative breast cancer), and is promising for the preparation of a drug for preventing and / or treating triple-negative breast cancer. The present invention is also the first to discover that an androgen receptor proteolytic agent can be used in combination with a targeted drug (including a PI3Kα inhibitor, a PARP inhibitor), an immunotherapy drug, or a chemotherapy drug to effectively prevent and / or treat triple-negative breast cancer, and is promising for the preparation of a drug for preventing and / or treating triple-negative breast cancer.

[0032] The definitions of terms used in the present invention are as follows: Unless otherwise specified, the initial definition provided by a group, radical or term in the text applies to the group or term throughout the entire specification, and any term not specifically defined in the text shall have the meaning that a person skilled in the art would have based on the disclosure and context.

[0033] In the present invention, "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, such as, for example, phenyl or naphthyl groups. The aromatic ring may be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and at the same time, the point of attachment to the parent must be on a carbon atom in the ring having a conjugated pi-electron system.

[0034] The term "heteroaromatic ring" refers to a heteroaromatic group containing one or more heteroatoms. The heteroatoms referred to here include oxygen, sulfur and nitrogen. Examples include a furyl group, a thienyl group, a pyridyl group, a pyrazolyl group, a pyrrolyl group, an N-alkylpyrrolyl group, a pyrimidinyl group, a pyrazinyl group, an imidazolyl group, and a tetrazolyl group. The ring of the heteroaromatic group may be condensed with a ring of an aryl group, a heterocyclic group or a cycloalkyl group, and the ring bonded to the parent structure is a ring of the heteroaromatic group.

[0035] In the present invention, an agent that degrades the androgen receptor targets means an agent that degrades the androgen receptor.

[0036] By "pharmaceutical acceptable" it is meant that the carrier, vehicle, diluent, auxiliary material and / or salt formed is chemically or physically compatible with the other ingredients that normally make up the drug dosage form and physiologically compatible with the receptor.

[0037] "Salt" refers to an acidic and / or basic salt formed by combining a compound or its stereoisomer with an inorganic and / or organic acid and / or base, including zwitterionic salts (internal salts) and further including quaternary ammonium salts, such as alkylammonium salts. These salts may be obtained directly in the final isolation and purification of the compound. They may also be obtained by mixing the compound or its stereoisomer with an appropriate amount of acid or base (e.g., equal equivalents). These salts may be obtained by forming a precipitate in a solution and collecting it by filtration, or by recovering it after evaporation of the solvent, or by reacting in an aqueous medium and then lyophilizing it. The salts described in this invention may be the hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, butanedioate, oxalate, malate, succinate, fumarate, maleate, tartrate, or trifluoroacetate salts of the compound.

[0038] "Solvate" means a solvate of a compound of the invention with a solvent, including, but not limited to, water, ethanol, methanol, isopropanol, propylene glycol, tetrahydrofuran, and dichloromethane.

[0039] Naturally, based on the above content of the present invention, various other forms of modifications, substitutions or changes can be made in light of general technical knowledge and conventional means in this field, on the premise that they do not deviate from the above basic technical idea of ​​the present invention.

[0040] The above contents of the present invention will be described in more detail below by specific embodiments in the form of examples. However, it should not be understood that the scope of the above subject matter of the present invention is limited to the following examples. Any technology realized based on the above contents of the present invention belongs to the scope of the present invention. [Brief description of the drawings]

[0041] [Figure 1]FIG. 1 shows the growth inhibitory effect of MDA-MB-453 cells by combined administration of Compound 279 and Alpelisib. [Diagram 2] FIG. 2 shows the growth inhibitory effect of MDA-MB-453 cells by combined administration of Compound 279 and alpelisib. [Diagram 3] FIG. 3 shows the growth inhibitory effect of MDA-MB-453 cells by combined administration of Compound 281 and alpelisib. [Figure 4] FIG. 4 shows the growth inhibitory effect of MDA-MB-453 cells by combined administration of Compound 281 and alpelisib. [Diagram 5] FIG. 5 shows the growth inhibitory effect of MDA-MB-453 cells by combined administration of Compound 282 and alpelisib. [Figure 6] FIG. 6 shows the growth inhibitory effect of MDA-MB-453 cells by combined administration of Compound 282 and alpelisib. [Figure 7] FIG. 7 shows the growth inhibitory effect of MDA-MB-453 cells by combined administration of ARV-110 and alpelisib. [Figure 8] FIG. 8 shows the growth inhibitory effect of MDA-MB-453 cells by combined administration of ARV-110 and alpelisib. [Figure 9] FIG. 9 shows the growth inhibitory effect of MDA-MB-453 cells by combined administration of ARV-766 and alpelisib. [Figure 10] FIG. 10 shows the growth inhibitory effect of MDA-MB-453 cells by combined administration of ARV-766 and alpelisib. [Figure 11] FIG. 11 shows the growth inhibitory effect of MDA-MB-453 cells by combined administration of Compound 279 and Duvelisib. [Figure 12] FIG. 12 shows the growth inhibitory effect of MDA-MB-453 cells by combined administration of Compound 279 and duvelisib. [Figure 13] FIG. 13 shows the growth inhibitory effect of MDA-MB-453 cells by combined administration of Compound 281 and duvelisib. [Figure 14] FIG. 14 shows the growth inhibitory effect of MDA-MB-453 cells by combined administration of Compound 281 and duvelisib. [Figure 15] FIG. 15 shows the growth inhibitory effect of MDA-MB-453 cells by combined administration of Compound 282 and duvelisib. [Figure 16] FIG. 16 shows the growth inhibitory effect of MDA-MB-453 cells by combined administration of Compound 282 and duvelisib. [Figure 17] FIG. 17 shows the growth inhibitory effect of MDA-MB-453 cells by combined administration of ARV-110 and duvelisib. [Figure 18] FIG. 18 shows the growth inhibitory effect of MDA-MB-453 cells by combined administration of ARV-110 and duvelisib. [Figure 19] FIG. 19 shows the growth inhibitory effect of MDA-MB-453 cells by combined administration of Compound 279 and Idelalisib. [Figure 20] FIG. 20 shows the growth inhibitory effect of MDA-MB-453 cells by combined administration of Compound 279 and idelalisib. [Figure 21] FIG. 21 shows the growth inhibitory effect of MDA-MB-453 cells by combined administration of Compound 281 and idelalisib. [Figure 22] FIG. 22 shows the growth inhibitory effect of MDA-MB-453 cells by combined administration of Compound 281 and idelalisib. [Diagram 23] FIG. 23 shows the growth inhibitory effect of MDA-MB-453 cells by combined administration of Compound 282 and idelalisib. [Figure 24] FIG. 24 shows the growth inhibitory effect of MDA-MB-453 cells by combined administration of Compound 282 and idelalisib. [Diagram 25] FIG. 25 shows the growth inhibitory effect of MDA-MB-453 cells by combined administration of ARV-110 and idelalisib. [Figure 26] FIG. 26 shows the growth inhibitory effect of MDA-MB-453 cells by combined administration of ARV-110 and idelalisib. [Figure 27] FIG. 27 shows the growth inhibitory effect of MDA-MB-453 cells by combined administration of ARV-766 and idelalisib. [Figure 28] FIG. 28 shows the growth inhibitory effect of MDA-MB-453 cells by combined administration of ARV-766 and idelalisib. [Figure 29] FIG. 29 shows the growth inhibitory effect of MDA-MB-453 cells by combined administration of Compound 279 and Paclitaxel. [Diagram 30] FIG. 30 shows the growth inhibitory effect of MDA-MB-453 cells by combined administration of Compound 279 and paclitaxel. [Diagram 31] FIG. 31 shows the growth inhibitory effect of MDA-MB-453 cells by combined administration of Compound 281 and paclitaxel. [Diagram 32] FIG. 32 shows the growth inhibitory effect of MDA-MB-453 cells by combined administration of Compound 282 and paclitaxel. [Diagram 33] FIG. 33 shows the growth inhibitory effect of MDA-MB-453 cells by combined administration of ARV-110 and paclitaxel. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0042] All the materials and equipment used in the present invention are conventional products and were purchased from commercial sources.

[0043] Example 1: Therapeutic effect of androgen receptor protein degrading agent on triple-negative breast cancer (in vitro experiment) 1. Experimental Method Triple-negative breast cancer MDA-MB-453 cells in the logarithmic growth phase were cultured at 4 × 10 3 The cells were seeded in a 96-well culture plate at a concentration of 1000 cells / well. The cells were then incubated at 37°C, 5% CO 2The wells were incubated for 24 or 48 hours in an incubator under conditions of concentration and saturated humidity. The negative control wells were added with RPMI 1640 cell culture medium containing 10% fetal bovine serum in the same volume as the drug. After 24 or 48 hours of incubation, the AR PROTACs Compound 162, Compound 177, Compound 230, Compound 259, Compound 279, Compound 281, Compound 282, Compound 325, Compound 357, Compound 400, ARV-110, ARV-766 and the AR inhibitor HC-1119 were added to the 96-well plate, respectively. The concentrations of compound 177, compound 230, compound 259, compound 279, compound 281, compound 282, compound 325, compound 357, compound 400, ARV-110, and ARV-766 are 0 μM, 0.002 μM, 0.005 μM, 0.014 μM, 0.041 μM, 0.123 μM, 0.370 μM, 1.111 μM, 3.333 μM, or 10 μM. The concentrations of HC-1119 are 0 μM, 1.23 μM, 3.70 μM, 11.11 μM, 33.33 μM, or 100 μM.

[0044] After adding the drugs and incubating for 7 to 10 days, 10 μL of CCK-8 was added to each well and the wells were incubated for 2 hours. The optical density (OD) of each well was measured at 450 nm using a microplate reader. Using Prism software, the survival rate was calculated by the following formula: Relative survival rate = (OD value of drug-treated well / OD value of control well) × 100%. Alternatively, 100 μL of medium was aspirated and discarded from each well, and 50 μL of CTG was added. The wells were shaken in the dark for 2 min, left to stand for 10 min, and read in luminescence mode using a microplate reader. Using Prism software, the survival rate was calculated by the following formula: Relative survival rate = (RLU value of drug-treated well / RLU value of control well) × 100%.

[0045] 2. Experimental Results (1) IC of Compound 177, Compound 230, Compound 259, Compound 279, Compound 281, Compound 282, Compound 325, Compound 357, Compound 400, ARV-110, and ARV-766 in MDA-MB-453 cells 50 Measurement IC of Compound 177, Compound 230, Compound 259, Compound 279, Compound 281, Compound 282, Compound 325, Compound 357, Compound 400, ARV-110, and ARV-766 in MDA-MB-453 cells 50 The measurement results are shown in Table 1. As the judgment criteria, when IC50≦2μM, it is marked as A, and when IC50>2μM, it is marked as B. From Table 1, it can be seen that compound 177, compound 230, compound 259, compound 279, compound 281, compound 282, compound 325, compound 357, compound 400, ARV-110, and ARV-766 have different degrees of inhibitory effect on the proliferation of MDA-MB-453 cells, and can be used for the effective treatment of triple negative breast cancer.

[0046] [Table 1]

[0047] (2) IC of HC-1119 in MDA-MB-453 cells 50 Measurement IC of HC-1119 in MDA-MB-453 cells 50 The measurement results are shown in Table 1. As a judgment criterion, when IC50≦2μM, it is indicated as A, and when IC50>2μM, it is indicated as B. As can be seen from Table 1, the inhibitory effect of HC-1119 on MDA-MB-453 cell proliferation is small, indicating that the therapeutic effect of the AR inhibitor HC-1119 on triple-negative breast cancer is obviously weaker than that of AR PROTACs Compound 177, Compound 230, Compound 259, Compound 279, Compound 281, Compound 282, Compound 325, Compound 357, Compound 400, ARV-110, and ARV-766.

[0048] Example 2: Therapeutic effect of triple-negative breast cancer by combination of androgen receptor proteolytic agent and PI3K inhibitor alpelisib (in vitro experiment) 1. Experimental Method Triple-negative breast cancer MDA-MB-453 cells in the logarithmic growth phase were cultured at 4 × 10 3The cells were seeded in a 96-well culture plate at a concentration of 1000 cells / well. The cells were then incubated at 37°C, 5% CO 2 The plates were incubated for 24 hours in an incubator under conditions of concentration and saturated humidity. The negative control wells were added with RPMI 1640 cell culture medium containing 10% fetal bovine serum in the same volume as the drug. After 24 hours of incubation, the drug AR PROTACs Compound 279, Compound 281, Compound 282, ARV-110, ARV-766, and the PI3K inhibitor alpelisib were added to the 96-well plate one after the other.

[0049] The concentrations of Compound 279, Compound 281, Compound 282, ARV-110, and ARV-766 are 0 μM, 0.002 μM, 0.005 μM, 0.014 μM, 0.041 μM, 0.123 μM, 0.370 μM, 1.111 μM, 3.333 μM, or 10 μM. The concentrations of Alpelisib are 0 μM, 0.123 μM, 0.370 μM, 1.111 μM, 3.333 μM, or 10 μM.

[0050] After adding the drugs and incubating for 7 days, 10 μL of CCK-8 was added to each well, followed by culturing for 2 hours. The absorbance value (OD) of each well was measured at a wavelength of 450 nm using a microplate reader. Using Prism software, the survival rate was calculated by the following formula: relative survival rate = (OD value of drug-treated well / OD value of control well) × 100%. Alternatively, 100 μL of medium was aspirated from each well and discarded, and 50 μL of CTG was added. The plates were shaken in the dark for 2 min, left to stand for 10 min, and read in luminescence mode using a microplate reader. Using Prism software, the survival rate was calculated by the following formula: relative survival rate = (RLU value of drug-treated well / RLU value of control well) × 100%. Furthermore, the combination index (CI) of the drugs was used for the evaluation. As a criterion, when CI<1, the combined administration was considered to have a synergistic effect.

[0051] 2. Experimental Results (1) The results of the combined administration of compound 279, compound 281, compound 282, ARV-110, ARV-766 and alpelisib are shown in Figures 1 to 10. As can be seen from these, when the molar ratio of compound 279, compound 281, compound 282, ARV-110, ARV-766 and alpelisib is 1:27 to 9:1, the combined administration of compound 279, compound 281, compound 282, ARV-110, ARV-766 and alpelisib has a synergistic effect on the inhibition of MDA-MB-453 cell proliferation, and can be used for the treatment of triple-negative breast cancer by the synergistic effect.

[0052] Example 3: Therapeutic effect of triple-negative breast cancer by combining androgen receptor proteolytic agent and PI3K inhibitor duvelisib (in vitro experiment) 1. Experimental Method Triple-negative breast cancer MDA-MB-453 cells in the logarithmic growth phase were cultured at 4 × 10 3 The cells were seeded in a 96-well culture plate at a concentration of 1000 cells / well. The cells were then incubated at 37°C, 5% CO 2 The plates were incubated for 24 hours in an incubator under conditions of concentration and saturated humidity. The negative control wells were added with RPMI 1640 cell culture medium containing 10% fetal bovine serum in the same volume as the drug. After 24 hours of incubation, the drug AR PROTACs Compound 279, Compound 281, Compound 282, ARV-110, and the PI3K inhibitor duvelisib were added to the 96-well plate one after the other.

[0053] The concentrations of Compound 279, Compound 281, Compound 282, and ARV-110 are 0 μM, 0.002 μM, 0.005 μM, 0.014 μM, 0.041 μM, 0.123 μM, 0.370 μM, 1.111 μM, 3.333 μM, or 10 μM. The concentrations of Duvelisib are 0 μM, 1.23 μM, 3.70 μM, 11.11 μM, 33.33 μM, or 100 μM.

[0054] After adding the drugs and incubating for 7 to 10 days, 10 μL of CCK-8 was added to each well and the wells were subsequently cultured for 2 hours. The absorbance value (OD) of each well was measured at a wavelength of 450 nm using a microplate reader. Using Prism software, the survival rate was calculated by the following formula: relative survival rate = (OD value of drug-treated well / OD value of control well) × 100%. Alternatively, 100 μL of medium was aspirated from each well and discarded, and 50 μL of CTG was added. The wells were shaken in the dark for 2 min, left to stand for 10 min, and read in luminescence mode using a microplate reader. Using Prism software, the survival rate was calculated by the following formula: relative survival rate = (RLU value of drug-treated well / RLU value of control well) × 100%. Furthermore, the survival rate was determined based on the combination index (CI) of the drugs. As a judgment criterion, when CI<1, the combined administration exerted a synergistic effect.

[0055] 2. Experimental Results The results of the combined administration of compound 279, compound 281, compound 282, ARV-110 and duvelisib are shown in Figures 11 to 18. As can be seen from these, when the molar ratio of compound 279, compound 281, compound 282, ARV-110 and duvelisib is 1:30 to 1:1.111, the combined administration of compound 279, compound 281, compound 282, ARV-110 and duvelisib has a synergistic effect on the inhibition of MDA-MB-453 cell proliferation, and can be used for the treatment of triple-negative breast cancer by synergistic effect.

[0056] Example 4: Therapeutic effect of triple-negative breast cancer by combination of androgen receptor proteolytic agent and PI3K inhibitor idelalisib (in vitro experiment) 1. Experimental Method Triple-negative breast cancer MDA-MB-453 cells in the logarithmic growth phase were cultured at 4 × 10 3 The cells were seeded in a 96-well culture plate at a concentration of 1000 cells / well. The cells were then incubated at 37°C, 5% CO 2The plates were incubated for 24 hours in an incubator under conditions of concentration and saturated humidity. The negative control wells were added with RPMI 1640 cell culture medium containing 10% fetal bovine serum in the same volume as the drug. After 24 hours of incubation, the drug AR PROTACs Compound 279, Compound 281, Compound 282, ARV-110, ARV-766, and the PI3K inhibitor idelalisib were added to the 96-well plate one after the other.

[0057] The concentrations of Compound 279, Compound 281, Compound 282, ARV-110, and ARV-766 are 0 μM, 0.002 μM, 0.005 μM, 0.014 μM, 0.041 μM, 0.123 μM, 0.370 μM, 1.111 μM, 3.333 μM, or 10 μM. The concentrations of Idelalisib are 0 μM, 1.23 μM, 3.70 μM, 11.11 μM, 33.33 μM, or 100 μM.

[0058] After adding the drugs and incubating for 7 to 10 days, 10 μL of CCK-8 was added to each well and the wells were subsequently cultured for 2 hours. The absorbance value (OD) of each well was measured at a wavelength of 450 nm using a microplate reader. Using Prism software, the survival rate was calculated by the following formula: relative survival rate = (OD value of drug-treated well / OD value of control well) × 100%. Alternatively, 100 μL of medium was aspirated from each well and discarded, and 50 μL of CTG was added. The wells were shaken in the dark for 2 min, left to stand for 10 min, and read in luminescence mode using a microplate reader. Using Prism software, the survival rate was calculated by the following formula: relative survival rate = (RLU value of drug-treated well / RLU value of control well) × 100%. Furthermore, the survival rate was determined based on the combination index (CI) of the drugs. As a judgment criterion, when CI<1, the combined administration exerted a synergistic effect.

[0059] 2. Experimental Results The results of the combined administration of compound 279, compound 281, compound 282, ARV-110, ARV-766 and idelalisib are shown in Figures 19 to 28. As can be seen from these, when the molar ratio of compound 279, compound 281, compound 282, ARV-110, ARV-766 and idelalisib is 1:270 to 1:3.333, the combined administration of compound 279, compound 281, compound 282, ARV-110, ARV-766 and idelalisib has a synergistic effect on the inhibition of MDA-MB-453 cell proliferation, and can be used for the treatment of triple-negative breast cancer by synergistic effect.

[0060] Example 5: Therapeutic effect of triple-negative breast cancer by combining an androgen receptor proteolytic agent with the chemotherapy drug paclitaxel (in vitro experiment) 1. Experimental Method Triple-negative breast cancer MDA-MB-453 cells in the logarithmic growth phase were cultured at 4 × 10 3 The cells were seeded in a 96-well culture plate at a concentration of 1000 cells / well. The cells were then incubated at 37°C, 5% CO 2 The plates were incubated for 24 hours in an incubator under conditions of concentration and saturated humidity. The negative control wells were added with RPMI 1640 cell culture medium containing 10% fetal bovine serum in the same volume as the drug. After 24 hours of incubation, the drug AR PROTACs Compound 279, Compound 281, Compound 282, ARV-110, and the chemotherapy drug paclitaxel were added to the 96-well plate one after the other.

[0061] The concentrations of Compound 279, Compound 281, Compound 282, and ARV-110 are 0 μM, 0.002 μM, 0.005 μM, 0.014 μM, 0.041 μM, 0.123 μM, 0.370 μM, 1.111 μM, 3.333 μM, or 10 μM. The concentrations of Paclitaxel are 0 nM, 0.025 nM, 0.074 nM, 0.222 nM, 0.667 nM, or 2 nM.

[0062] After adding the drugs and incubating for 7 days, 10 μL of CCK-8 was added to each well, followed by culturing for 2 hours. The absorbance value (OD) of each well was measured at a wavelength of 450 nm using a microplate reader. Using Prism software, the survival rate was calculated by the following formula: relative survival rate = (OD value of drug-treated well / OD value of control well) × 100%. Alternatively, 100 μL of medium was aspirated from each well and discarded, and 50 μL of CTG was added. The plates were shaken in the dark for 2 min, left to stand for 10 min, and read in luminescence mode using a microplate reader. Using Prism software, the survival rate was calculated by the following formula: relative survival rate = (RLU value of drug-treated well / RLU value of control well) × 100%. Furthermore, the combination coefficient (CI) of the drugs was used for the judgment. As a judgment criterion, when CI<1, the combination administration was considered to have a synergistic effect.

[0063] 2. Experimental Results The results of the combined administration of compound 279, compound 281, compound 282, ARV-110 and paclitaxel are shown in Figures 19 to 36. As can be seen from these, when the molar ratio of compound 279, compound 281, compound 282, ARV-110 and paclitaxel is 20:1 to 5000:1, the combined administration of compound 279, compound 281, compound 282, ARV-110 and paclitaxel has a synergistic effect on the inhibition of MDA-MB-453 cell proliferation, and can be used for the treatment of triple-negative breast cancer by synergistic effect.

[0064] As described above, the present invention is the first to discover that an androgen receptor-targeted proteolytic agent can effectively prevent and / or treat triple-negative breast cancer (including androgen receptor-positive triple-negative breast cancer), and that the preparation of a drug for preventing and / or treating triple-negative breast cancer is promising. The present invention is also the first to discover that an androgen receptor proteolytic agent can be used in combination with a target drug (including a PI3Kα inhibitor and a PARP inhibitor), an immunotherapy drug, or a chemotherapy drug to effectively prevent and / or treat triple-negative breast cancer, and that the preparation of a drug for preventing and / or treating triple-negative breast cancer is promising.

Claims

1. Use of a combination of an androgen receptor-targeting degrader based on a dosamine-based E3 ligase ligand and a targeted drug in the preparation of a drug for preventing and / or treating triple-negative breast cancer.

2. The use according to claim 1, characterized in that the targeted drug is a PI3K inhibitor.

3. The use according to claim 2, characterized in that the PI3K inhibitor is a PI3Kα inhibitor.

4. The use according to claim 3, wherein the PI3K inhibitor is the following compound, or an optical isomer thereof, a tautomer thereof, a salt thereof, a prodrug thereof, a hydrate thereof, or a solvate thereof, characterized in that the compound is alpelisib, GDC-0077, TAK-117, AZD-8186, IPI-549, idelalisib, buparlisib, piralalisib, copanlisib, PX-866, paxalisib, duvelisib, umbralisib, taselisib, perifosine, buparlisib, dactolisib, CUDC-907, or voxtalisib.

5. The use according to claim 1, characterized in that the targeted drug is a PARP inhibitor.

6. 6. The use according to claim 5, characterized in that the PARP inhibitor is olaparib, rucaparib, talazopanib, niraparib, pamiparib or fluzoparib.

7. the targeted drug is alpelisib, and the molar ratio of the androgen receptor-targeting degrader to alpelisib is 1:27 to 3:1; Or, the targeted drug is duvelisib, and the molar ratio of the androgen receptor-targeting degrader to duvelisib is 1:30 to 1:10; Or the use according to any one of claims 1 to 5, characterized in that the targeted drug is idelalisib, and the molar ratio of the androgen receptor targeting degrader to idelalisib is 1:270 to 1:

90.

8. The use of a combination of an androgen receptor targeting degrader based on a dosamine-based E3 ligase ligand and an immunotherapy drug in the preparation of a drug for preventing and / or treating triple-negative breast cancer.

9. The use of a combination of an androgen receptor targeting degrader based on a dosamine-based E3 ligase ligand and a chemotherapy drug in the preparation of a drug for preventing and / or treating triple-negative breast cancer.

10. The use according to claim 9, characterized in that the chemotherapy drug is paclitaxel or 5-fluorouracil.

11. the chemotherapy drug is paclitaxel, and the molar ratio of the androgen receptor targeting degrader to paclitaxel is 20:1 to 5000:1; Or the use according to claim 10, characterized in that the chemotherapy drug is 5-fluorouracil, and the molar ratio of the androgen receptor targeting degrading agent to 5-fluorouracil is 1.85:1 to 5.54:

1.

12. The use according to any one of claims 1 to 11, characterized in that the degrading agent targeting the androgen receptor is a PROTAC bifunctional chimeric molecule as shown in formula (I) or an optical isomer thereof, a tautomer thereof, or a pharma- ceutically acceptable salt thereof. (wherein ARB is a ligand of the androgen receptor, L is a linker, and U is a ligand of a dosamine-based E3 ligase).

13. The use of claim 12, wherein U is a CRBN system E3 ligase ligand and has the following structure: (wherein E is an unsubstituted or substituted benzene ring, a 5-membered aromatic heterocycle, a 6-membered aromatic heterocycle, a benzoaromatic heterocycle, or an unsaturated benzoheterocycle; E Ｘ is none, halogen, oxygen, sulfur, nitrogen, carbonyl group, -(CH ２ ) - and E Ｙ is nothing, H, or a carbonyl group.

14. 14. The use according to claim 12 or 13, characterized in that the structure of U is selected from the following:

15. The use according to claim 12, characterized in that the PROTAC bifunctional chimeric molecule is selected from ARV-110, ARV-766, HP518, AC0176, GT20029, ASN-1780, ARD-2128, ARD-2585.

16. The use according to claim 12, characterized in that the structure of the PROTAC bifunctional chimeric molecule is as shown in formula (II): (wherein X is F, Cl, Br, Me, CF ３ is selected from Y is selected from CH or N; W is selected from O, S, NMe; Ring A is R １ , R ２ , R ３ and / or R ４ cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, R １ , R ２ , R ３ , R ４ , R ５ are each independently selected from hydrogen and Me; Ring B is selected from a 5-membered aromatic heterocycle, a 6-membered aromatic ring, and a 6-membered aromatic heterocycle; G １ , G ２ , G ３ are each independently CR ６ , N, where R ６ is selected from H, a halogen, and a hydroxy group; n1, n2, n3, n4, n5, and n6 are each independently selected from 1 or 2; M is CR ７ R ８ where R ７ , R ８ are each independently selected from H and Me; Z is selected from H, F, Cl, Me.

17. The use according to claim 12, characterized in that the structure of the PROTAC bifunctional chimeric molecule is selected from the following:

18. The use according to any one of claims 1 to 11, characterized in that the triple-negative breast cancer is androgen receptor positive triple-negative breast cancer.

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