Classifications

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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4965—Non-condensed pyrazines
  • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
• • A—HUMAN NECESSITIES
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  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• • A—HUMAN NECESSITIES
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  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
  • A61K31/52—Purines, e.g. adenine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
• • A—HUMAN NECESSITIES
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  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
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  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/545—Heterocyclic compounds
• • A—HUMAN NECESSITIES
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  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
• • A—HUMAN NECESSITIES
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Definitions

• the invention belongs to the field of medicine. Specifically, the invention relates to a medicine for treating triple-negative breast cancer.
• Breast cancer has become the most common female malignant tumor in the world. Its morbidity and mortality rate are the first among female tumors, which seriously threatens and harms women's physical and mental health. Different types of breast cancer have significantly different biological characteristics and clinical manifestations. Currently, immunohistochemistry methods are mainly used clinically, based on estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2.
• ER estrogen receptor
• PR progesterone receptor
• human epidermal growth factor receptor 2 human epidermal growth factor receptor 2.
• HER-2 test results divide breast cancer into four molecular subtypes: luminal type A (ER positive or PR positive, HER-2 negative, low expression of Ki67), luminal type B (ER positive or PR positive, HER-2 is also positive), HER-2 overexpression type (ER, PR negative, HER-2 positive, mostly high expression of Ki67) and basal-like type (ER, PR, HER-2 negative).
• TNBC triple negative breast cancer
• Cyclophosphamide, doxorubicin, and 5-fluorouracil (5-FU) have always been recognized as first-line chemotherapy drugs for the treatment of advanced breast cancer.
• drugs such as paclitaxel
• paclitaxel and cisplatin it can also be used as a first-line chemotherapy option.
• the therapeutic efficacy of these chemotherapy drugs still needs to be further improved.
• Androgen receptor belongs to the nuclear receptor family and is a type of ligand-dependent transcription factor. Abnormal regulation of the AR signaling pathway plays an important role in the occurrence and development of prostate cancer. Studies have shown that castration-resistant prostate cancer (CRPC) still relies on the role of AR.
• Protein degradation targeting chimeras have received widespread attention as small molecules that can induce the degradation of target proteins. As bifunctional molecules, PROTACs include a small molecule compound that can bind to the target protein (protein of interest, POI), introduce a linking group at the appropriate position, and then connect to a small molecule compound that can bind to ubiquitin protease.
• the obtained small molecule probe can bind to the target protein and ubiquitin protease at the same time, thereby promoting the ubiquitination of the target protein.
• the multi-ubiquitinated protein can be recognized and degraded by the proteasome.
• protein degradation-targeted chimeras AR PROTACs
• AR PROTACs protein degradation-targeted chimeras
• Hormone receptors are degraded, thereby achieving the effect of treating prostate cancer and other related diseases that are regulated by androgen receptors.
• One object of the present invention is to provide the use of an androgen receptor-targeting degrader based on a rimidine E3 ligase ligand in the preparation of drugs for the prevention and/or treatment of triple-negative breast cancer.
• Another object of the present invention is to provide an androgen receptor-targeting degrader based on rimidine E3 ligands for use in combination with targeted drugs (including PI3K ⁇ inhibitors, PARP inhibitors), immunotherapy drugs, or chemotherapy drugs. Use in the preparation of drugs for the prevention and/or treatment of triple-negative breast cancer.
• the present invention specifically provides the use of an androgen receptor-targeting degrader based on a rimidine E3 ligase ligand in the preparation of drugs for preventing and/or treating triple-negative breast cancer.
• the degradation agent targeting the androgen receptor is a PROTAC bifunctional chimera molecule represented by formula (I), or its optical isomer, its tautomer, or its pharmaceutically acceptable salt. :
• ARB is the ligand of androgen receptor
• L is the linker
• U is the ligand of E3 ligase.
• U is a CRBN-like E3 ligase ligand with the following structure:
• E is unsubstituted and substituted benzene rings, five-membered aromatic heterocycles, six-membered aromatic heterocycles, benzoaromatic heterocycles, and benzene unsaturated heterocycles;
• E X is none, halogen, oxygen, sulfur, nitrogen, carbonyl, -(CH 2 )-;
• E Y is none, H, carbonyl group.
• the U is a CRBN-like E3 ligase ligand.
• PROTAC bifunctional chimera molecule is selected from ARV-110, ARV-766, HP518, AC0176, GT20029, ASN-1780, ARD-2128, ARD-2585.
• X is selected from F, Cl, Br, Me, CF 3 ;
• Y is selected from CH or N;
• W is selected from O, S, NMe
• Ring A is selected from the following groups substituted by R 1 , R 2 , R 3 and/or R 4 : cyclopropane, cyclopropane Butane, cyclopentane, cyclohexane, cycloheptane;
• R 1 , R 2 , R 3 , R 4 , R 5 are each independently selected from hydrogen, Me;
• Ring B is selected from 5-membered aromatic heterocycle, 6-membered aromatic ring, and 6-membered aromatic heterocycle;
• G 1 , G 2 , G 3 are each independently selected from CR 6 , N; wherein R 6 is selected from H, halogen, and hydroxyl;
• n1, n2, n3, n4, n5 and n6 are independently selected from 1 or 2;
• M is selected from CR 7 R 8 , where R 7 and R 8 are independently selected from H, Me;
• Z is selected from H, F, Cl, Me.
• the structure of the PROTAC bifunctional chimera molecule is selected from:
• the triple-negative breast cancer is androgen receptor-positive triple-negative breast cancer.
• the present invention also provides the use of a degradation agent targeting the androgen receptor in combination with a targeted drug in preparing a drug for preventing and/or treating triple-negative breast cancer.
• the targeted drug is a PI3K inhibitor.
• the PI3K inhibitor is a PI3K ⁇ inhibitor.
• the PI3K inhibitor is the following compound, or its optical isomer, its tautomer, its salt, its prodrug, its hydrate, its solvate: Alpelisib, GDC-0077, TAK- 117. AZD-8186, IPI-549, Idelalisib, Buparlisib, Pilaralisib, Copanlisib, PX-866, Paxalisib, Duvelisib, Umbralisib, Taselisib, Perifosine, Buparlisib, Dactolisib, CUDC-907, Voxtalisib.
• the targeted drug is a PARP inhibitor.
• the PARP inhibitor is olaparib, rucaparib, talazoparib, niraparib, pamiparib or fluzoparib.
• the targeted drug is Alpelisib
• the molar ratio of the androgen receptor-targeting degrader to Alpelisib is 1:27-3:1;
• the targeted drug is Duvelisib
• the molar ratio of the androgen receptor-targeting degrader to Duvelisib is 1:30-1:10;
• the targeted drug is Idelalisib
• the molar ratio of the androgen receptor-targeting degradation agent to Idelalisib is 1:270-1:90.
• the present invention also provides the use of a degradation agent targeting the androgen receptor in combination with an immunotherapy drug in preparing a drug for preventing and/or treating triple-negative breast cancer.
• the present invention also provides the use of a degradation agent targeting the androgen receptor in combination with a chemotherapy drug in preparing a drug for preventing and/or treating triple-negative breast cancer.
• the chemotherapy drug is Paclitaxel or 5-Fluorouracil.
• the chemotherapy drug is Paclitaxel
• the molar ratio of the androgen receptor-targeting degrader to Paclitaxel is 20:1-5000:1;
• the chemotherapeutic drug is 5-Fluorouracil
• the molar ratio of the androgen receptor-targeting degrading agent to 5-Fluorouracil is 1.85:1-5.54:1.
• the triple-negative breast cancer is androgen receptor-positive triple-negative breast cancer.
• the androgen receptor degrading agent is the above-mentioned androgen receptor degrading agent.
• the present invention discovers for the first time that a protein degradation agent targeting androgen receptors can effectively prevent and/or treat triple-negative breast cancer (including androgen receptor-positive triple-negative breast cancer). It has good prospects as a cancer drug.
• the present invention has discovered for the first time that the combined use of an androgen receptor protein degrading agent and targeted drugs (including PI3K ⁇ inhibitors, PARP inhibitors), immunotherapy drugs or chemotherapy drugs can effectively prevent and/or treat triple-negative breast cancer. There is good promise among drugs for the prevention and/or treatment of triple-negative breast cancer.
• aromatic ring refers to an all-carbon monocyclic or fused polycyclic ring with a conjugated ⁇ electron system.
• Cyclic (i.e., rings sharing adjacent pairs of carbon atoms) groups such as phenyl and naphthyl.
• the aromatic ring can be fused to other cyclic groups (including saturated and unsaturated rings), but it cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of connection to the parent must be at a point with a conjugated ⁇ electron system. on the carbon atoms in the ring.
• Heteroaromatic ring refers to a heteroaromatic group containing one to more heteroatoms. Heteroatoms referred to here include oxygen, sulfur and nitrogen. For example, furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc.
• the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring attached to the parent structure is the heteroaryl ring.
• the degradation agent targeting androgen receptor refers to the androgen receptor degradation agent.
• “Pharmaceutically acceptable” means a carrier, carrier, diluent, excipient, and/or salt formed that is generally chemically or physically compatible with the other ingredients constituting a pharmaceutical dosage form and is physiologically compatible with Receptor compatible.
• Salt refers to an acidic and/or basic salt formed by a compound or its stereoisomer with inorganic and/or organic acids and/or bases. It also includes zwitterionic salts (inner salts) and quaternary ammonium salts. , such as alkylammonium salts. These salts can be obtained directly from the final isolation and purification of the compounds. It can also be obtained by appropriately mixing the compound, or its stereoisomer, with a certain amount of acid or base (for example, equivalent amounts). These salts may form a precipitate in the solution and be collected by filtration, or may be recovered after evaporation of the solvent, or may be obtained by reacting in an aqueous medium and then freeze-drying.
• the salt mentioned in the present invention can be the hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, butylene salt of the compound. salt, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate.
• solvent refers to a compound of the present invention forming a solvate with a solvent, wherein the solvent includes (but is not limited to): water, ethanol, methanol, isopropyl alcohol, propylene glycol, tetrahydrofuran, and methylene chloride.
• Figure 1 The effect of compound 279 and Alpelisib combined to inhibit the growth of MDA-MB-453 cells.
• Figure 2 The effect of compound 279 and Alpelisib combined to inhibit the growth of MDA-MB-453 cells.
• Figure 3 The effect of compound 281 and Alpelisib combined to inhibit the growth of MDA-MB-453 cells.
• Figure 4 The effect of compound 281 and Alpelisib combined to inhibit the growth of MDA-MB-453 cells.
• Figure 5 The effect of compound 282 and Alpelisib combined to inhibit the growth of MDA-MB-453 cells.
• Figure 6 The effect of compound 282 and Alpelisib combined to inhibit the growth of MDA-MB-453 cells.
• Figure 7 The effect of ARV-110 and Alpelisib combined to inhibit the growth of MDA-MB-453 cells.
• Figure 8 The effect of ARV-110 and Alpelisib combined to inhibit the growth of MDA-MB-453 cells.
• Figure 9 The effect of ARV-766 and Alpelisib combined to inhibit the growth of MDA-MB-453 cells.
• Figure 10 The effect of ARV-766 and Alpelisib combined to inhibit the growth of MDA-MB-453 cells.
• Figure 11 The combined use of compound 279 and Duvelisib inhibits the growth of MDA-MB-453 cells.
• Figure 12 The effect of compound 279 and Duvelisib combined to inhibit the growth of MDA-MB-453 cells.
• Figure 13 The effect of compound 281 and Duvelisib combined to inhibit the growth of MDA-MB-453 cells.
• Figure 14 The effect of compound 281 and Duvelisib combined to inhibit the growth of MDA-MB-453 cells.
• Figure 15 The effect of compound 282 and Duvelisib combined to inhibit the growth of MDA-MB-453 cells.
• Figure 16 The effect of compound 282 and Duvelisib combined to inhibit the growth of MDA-MB-453 cells.
• Figure 17 The effect of ARV-110 and Duvelisib combined to inhibit the growth of MDA-MB-453 cells.
• Figure 18 The effect of ARV-110 and Duvelisib combined to inhibit the growth of MDA-MB-453 cells.
• Figure 19 The effect of compound 279 and Idelalisib combined to inhibit the growth of MDA-MB-453 cells.
• Figure 20 The effect of combined use of compound 279 and Idelalisib on inhibiting the growth of MDA-MB-453 cells.
• Figure 21 The effect of compound 281 and Idelalisib combined to inhibit the growth of MDA-MB-453 cells.
• Figure 22 The effect of compound 281 and Idelalisib combined to inhibit the growth of MDA-MB-453 cells.
• Figure 23 The effect of compound 282 and Idelalisib combined to inhibit the growth of MDA-MB-453 cells.
• Figure 24 The effect of compound 282 and Idelalisib combined to inhibit the growth of MDA-MB-453 cells.
• Figure 25 The effect of ARV-110 and Idelalisib combined to inhibit the growth of MDA-MB-453 cells.
• Figure 26 The effect of ARV-110 and Idelalisib combined to inhibit the growth of MDA-MB-453 cells.
• Figure 27 The effect of ARV-766 and Idelalisib combined to inhibit the growth of MDA-MB-453 cells.
• Figure 28 The effect of ARV-766 and Idelalisib combined to inhibit the growth of MDA-MB-453 cells.
• Figure 29 The effect of compound 279 and Paclitaxel combined to inhibit the growth of MDA-MB-453 cells.
• Figure 30 The effect of compound 279 and Paclitaxel combined to inhibit the growth of MDA-MB-453 cells.
• Figure 31 The effect of compound 281 and Paclitaxel combined to inhibit the growth of MDA-MB-453 cells.
• Figure 32 Combination of compound 282 and Paclitaxel inhibits the growth of MDA-MB-453 cells.
• Figure 33 The effect of ARV-110 and Paclitaxel combined to inhibit the growth of MDA-MB-453 cells.
• the raw materials and equipment used in the present invention are all known products and are obtained by purchasing commercially available products.
• Example 1 Effect of androgen receptor protein degrading agent in treating triple-negative breast cancer (in vitro experiment)
• Triple-negative breast cancer MDA-MB-453 cells in the logarithmic growth phase were taken and seeded in a 96-well culture plate at a concentration of 4 ⁇ 10 3 cells/well. And incubate for 24 or 48 hours in an incubator at 37°C, 5% CO2 concentration and saturated humidity conditions. Add the same volume of RPMI 1640 cell culture medium containing 10% fetal bovine serum to the negative control well as the drug.
• 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 AR were inhibited Agent HC-1119 was 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 ⁇ M, 0.002 ⁇ M, 0.005 ⁇ M, 0.014 ⁇ M, 0.041 ⁇ M, 0.123 ⁇ M, 0.370 ⁇ M, 1.111 ⁇ M, 3.333 ⁇ M or 10 ⁇ M; the concentration of HC-1119 is: 0 ⁇ M, 1.23 ⁇ M, 3.70 ⁇ M, 11.11 ⁇ M, 33.33 ⁇ M or 100 ⁇ M.
• the IC 50 measurement results of compound 177, compound 230, compound 259, compound 279, compound 281, compound 282, compound 325, compound 357, compound 400, ARV-110, and ARV-766 on MDA-MB-453 cells are shown in Table 1 As shown, the judgment standard is as follows: when IC50 ⁇ 2 ⁇ M, it is expressed as A; when IC50>2 ⁇ M, it is expressed as B. As can be seen from Table 1: 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 effects on the growth of MDA-MB-453 cells. The inhibitory effect can be used to effectively treat triple-negative breast cancer.
• IC 50 measurement results of HC-1119 on MDA-MB-453 cells are shown in Table 1.
• the judgment criteria are as follows: when IC50 ⁇ 2 ⁇ M, it is expressed as A, when IC50 > 2 ⁇ M, it is expressed as B. It can be seen from Table 1 that HC-1119 has a poor inhibitory effect on the growth of MDA-MB-453 cells, indicating that the effect of the AR inhibitor HC-1119 in treating triple-negative breast cancer is significantly weaker than the AR PROTACs Compound 177, Compound 230, Compound 259, Compound 279, Compound 281, Compound 282, Compound 325, Compound 357, Compound 400, ARV-110, ARV-766.
• Example 2 Effect of combined use of androgen receptor protein degrader and PI3K inhibitor Alpelisib in the treatment of triple-negative breast cancer (in vitro experiment)
• Triple-negative breast cancer MDA-MB-453 cells in the logarithmic growth phase were taken and seeded in a 96-well culture plate at a concentration of 4 ⁇ 10 3 cells/well. And incubate for 24 hours in an incubator at 37°C, 5% CO2 concentration and saturated humidity. Add the same volume of RPMI 1640 cell culture medium containing 10% fetal bovine serum to the negative control well as the drug. After incubation for 24 hours, the drugs AR PROTACs compound 279, compound 281, compound 282, ARV-110, ARV-766 and PI3K inhibitor Alpelisib were added to the 96-well plate.
• the concentrations of Compound 279, Compound 281, Compound 282, ARV-110, and ARV-766 are: 0 ⁇ M, 0.002 ⁇ M, 0.005 ⁇ M, 0.014 ⁇ M, 0.041 ⁇ M, 0.123 ⁇ M, 0.370 ⁇ M, 1.111 ⁇ M, 3.333 ⁇ M, or 10 ⁇ M; Alpelisib Concentrations are: 0 ⁇ M, 0.123 ⁇ M, 0.370 ⁇ M, 1.111 ⁇ M, 3.333 ⁇ M or 10 ⁇ M.
• Example 3 Effect of combined use of androgen receptor protein degrader and PI3K inhibitor Duvelisib in the treatment of triple-negative breast cancer (in vitro experiment)
• Triple-negative breast cancer MDA-MB-453 cells in the logarithmic growth phase were taken and seeded in a 96-well culture plate at a concentration of 4 ⁇ 10 3 cells/well. And incubate for 24 hours in an incubator at 37°C, 5% CO2 concentration and saturated humidity. Add the same volume of RPMI 1640 cell culture medium containing 10% fetal bovine serum to the negative control well as the drug. After incubation for 24 hours, the drugs AR PROTACs compound 279, compound 281, compound 282, ARV-110, and PI3K inhibitor Duvelisib were added to the 96-well plate.
• the concentrations of compound 279, compound 281, compound 282, and ARV-110 are: 0 ⁇ M, 0.002 ⁇ M, 0.005 ⁇ M, 0.014 ⁇ M, 0.041 ⁇ M, 0.123 ⁇ M, 0.370 ⁇ M, 1.111 ⁇ M, 3.333 ⁇ M, or 10 ⁇ M; the concentration of Duvelisib is: 0 ⁇ M , 1.23 ⁇ M, 3.70 ⁇ M, 11.11 ⁇ M, 33.33 ⁇ M or 100 ⁇ M.
• Example 4 Effect of combined use of androgen receptor protein degrader and PI3K inhibitor Idelalisib in the treatment of triple-negative breast cancer (in vitro experiment)
• Triple-negative breast cancer MDA-MB-453 cells in the logarithmic growth phase were taken and seeded in a 96-well culture plate at a concentration of 4 ⁇ 10 3 cells/well. And incubate for 24 hours in an incubator at 37°C, 5% CO2 concentration and saturated humidity. Add the same volume of RPMI 1640 cell culture medium containing 10% fetal bovine serum to the negative control well as the drug. After incubation for 24 hours, the drugs AR PROTACs compound 279, compound 281, compound 282, ARV-110, ARV-766 and PI3K inhibitor Idelalisib were added to the 96-well plate.
• concentrations of compound 279, compound 281, compound 282, ARV-110, and ARV-766 are: 0 ⁇ M, 0.002 ⁇ M, 0.005 ⁇ M, 0.014 ⁇ M, 0.041 ⁇ M, 0.123 ⁇ M, 0.370 ⁇ M, 1.111 ⁇ M, 3.333 ⁇ M, or 10 ⁇ M; Idelalisib Concentrations are: 0 ⁇ M, 1.23 ⁇ M, 3.70 ⁇ M, 11.11 ⁇ M, 33.33 ⁇ M or 100 ⁇ M.
• Example 5 The effect of combined use of an androgen receptor protein degrading agent and the chemotherapy drug Paclitaxel in the treatment of triple-negative breast cancer (in vitro experiment)
• Triple-negative breast cancer MDA-MB-453 cells in the logarithmic growth phase were taken and seeded in a 96-well culture plate at a concentration of 4 ⁇ 10 3 cells/well. And incubate for 24 hours in an incubator at 37°C, 5% CO2 concentration and saturated humidity. Add the same volume of RPMI 1640 cell culture medium containing 10% fetal bovine serum to the negative control well as the drug. After incubation for 24 hours, the drugs AR PROTACs compound 279, compound 281, compound 282, ARV-110 and the chemotherapy drug Paclitaxel were added to the 96-well plate.
• the concentrations of compound 279, compound 281, compound 282, and ARV-110 are: 0 ⁇ M, 0.002 ⁇ M, 0.005 ⁇ M, 0.014 ⁇ M, 0.041 ⁇ M, 0.123 ⁇ M, 0.370 ⁇ M, 1.111 ⁇ M, 3.333 ⁇ M or 10 ⁇ M; the concentration of Paclitaxel is: 0nM , 0.025nM, 0.074nM, 0.222nM, 0.667nM or 2nM.
• the present invention has discovered for the first time that a protein degrading agent targeting the androgen receptor can effectively prevent and/or treat triple-negative breast cancer (including androgen receptor-positive triple-negative breast cancer). It has good prospects as a drug for triple-negative breast cancer.
• the present invention has discovered for the first time that the combined use of an androgen receptor protein degrading agent and targeted drugs (including PI3K ⁇ inhibitors, PARP inhibitors), immunotherapy drugs or chemotherapy drugs can effectively prevent and/or treat triple-negative breast cancer. There is good promise among drugs for the prevention and/or treatment of triple-negative breast cancer.

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