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Antibody protac conjugates

A technology of immunoconjugates and antibodies, applied in the direction of antibodies, anti-animal/human immunoglobulins, anti-tumor drugs, etc.

Pending Publication Date: 2020-12-25
DEV CENT FOR BIOTECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

While these prior art PROTACs are very useful, there is still a need for better PROTACs

Method used

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  • Antibody protac conjugates
  • Antibody protac conjugates
  • Antibody protac conjugates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Example 1: Preparation of Trastuzumab-BRD4-PROTAC-1

[0051] Synthesis of compound 2

[0052]

[0053] In this example, the BET inhibitor is OTX015, an orally bioavailable small molecule inhibitor of BRD2, BRD3, and BRD4 (EC 50 = 10 to 19 nM). OTX015 downregulates c-Myc expression and induces cell cycle arrest and apoptosis. Therefore, it has anti-proliferative effects on various solid tumors and leukemia.

[0054] Compound 2: To a mixture of OTX015(1) (0.2 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (1 mmol) in dimethylformamide (5 mL) was added potassium carbonate (0.6 mmol). The mixture was stirred at 50°C for 24 hours. After the reaction was completed, the reaction mixture was extracted with dichloromethane and water. Then, the organic layer was washed with brine and washed with MgSO 4 dry. The organic solvent was removed under reduced pressure. The residue was purified by column chromatography with methanol:dichloromethane (1:19) to afford compound 2 as a...

Embodiment 2

[0067] Example 2: Preparation of Trastuzumab-BRD4-PROTAC-2

[0068] Synthesis of Compound 8

[0069]

[0070] Compound 8: To a solution of 4-(N-maleimidomethyl)cyclohexane-1-carboxylic acid succinimide (SMCC) (0.75 mmol) in acetonitrile (7 mL) was added 1, 2-ethanedithiol (0.82 mmol). The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was extracted with dichloromethane and water. Then, the organic layer was washed with brine and washed with MgSO 4 dry. The organic solvent was removed under reduced pressure. The residue was purified by column chromatography with ethyl acetate:hexane (3:2) to afford compound 8 as a white solid (34.8% yield).

[0071] Synthesis of compound 9

[0072]

[0073] Compound 9: To a solution of compound 7 (0.02 mmol) in acetonitrile / dimethylformamide (1:1, 6 mL) was added compound 8 (0.04 mmol). The reaction mixture was stirred at room temperature for 16 hours. After th...

Embodiment 3

[0078] Example 3: Synthesis of a linear form of BRD4-PROTAC (17)

[0079] Figure 4 A possible synthetic scheme via the A-conjugated synthesis of ARV-825 is illustrated. Functional group modification of protein ligands or ligase conjugates is not easy. Furthermore, not all protein ligands or ligase conjugates have suitable functional groups for modification. In this example, the chlorine atom on OTX015 (the protein ligand of PROTAC ARV-825) was difficult to convert into another functional group, such as amino group. OTX015 or ARV-825 showed no reactivity under Buchwald reaction (palladium catalyzed coupling reaction) and Ullman reaction (copper catalyzed coupling reaction). Harsh reaction conditions, such as metal halide exchange, will lead to compound decomposition. According to the literature (EP1887008A1), different BRD4 inhibitor functional groups should be introduced at the outset. In other words, direct coupling of linkers to protein ligands or ligase conjugates wou...

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Abstract

An immunoconjugate having the Formula Ab-[L1-(A-L2-B)m]n, wherein: (a) Ab is an antibody or a binding fragment thereof; (b) L1 and L2 are each independently a linker, wherein L1 and L2 are the same ordifferent and wherein L1 links to L2; (c) A is a target-protein ligand / binder; (d) B is a ubiquitin ligase ligand / binder, and (e) n and m are independently integers from 1 to 8. The target protein includes kinase, G protein-coupled receptors, transcription factor, phosphatases, and RAS superfamily members.

Description

technical field [0001] The present invention relates to novel therapeutic agents based on ADC and PROTAC technologies. Background technique [0002] Antibodies have long been indispensable tools in basic research as well as in medical applications because of their high specificity and affinity for target antigens. A key feature of antibodies is their high specificity and their ability to bind the target antigen, which is labeled for removal by complement-dependent cytotoxicity (CDC) or antibody-dependent cell-mediated cytotoxicity (ADCC). Antibodies can also confer therapeutic benefit by binding to and inhibiting the function of a target antigen. However, many unmodified antibodies against tumor-specific antigens often lack therapeutic activity. Although some antibodies can alternatively be successfully used as homing missiles to deliver potent cytotoxic drugs in the form of antibody drug conjugates (ADCs), many ADCs have limited therapeutic potential and may require furth...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/68C07K16/30A61P35/00
CPCA61K47/6803A61K47/6851A61P35/00C07K16/32A61K47/6855A61K47/6863A61K47/6867A61K2039/505A61K47/6849
Inventor 庄士贤廖助彬孙玮廷梁镇显林文惠赖俊良林和昇
Owner DEV CENT FOR BIOTECHNOLOGY
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