745017-94-1

Usage

Uses

Used in Anticancer Applications:
MonoMethylauristatin F is used as a cytotoxic agent for the treatment of various types of cancer. Its potent antitumor effects are achieved through conjugation with a monoclonal antibody targeting internalizing, tumor-specific cell surface antigens. The stability of the linker in extracellular fluid and its cleavage by cathepsin once inside the tumor cell activate the anti-mitotic mechanism, leading to the inhibition of tumor growth.
Used in Biotechnological Applications:
In the biotechnology industry, MonoMethylauristatin F is used as a key component in the development of antibody-conjugated drugs. Its unique properties, such as the charged C-terminal phenylalanine and high toxicity, make it an ideal candidate for creating targeted therapies with improved efficacy and reduced side effects.
Used in Drug Delivery Systems:
MonoMethylauristatin F is employed in the design and development of novel drug delivery systems, specifically for antibody-conjugated drugs. These systems aim to enhance the delivery, bioavailability, and therapeutic outcomes of MMAF by utilizing protease-cleavable linkers that ensure the drug's release only upon internalization by the target tumor cells. This targeted approach minimizes damage to healthy cells and maximizes the drug's cytotoxic effects on cancer cells.

in vivo

The maximum tolerated dose in mice of MMAF (Monomethylauristatin F) (>16 mg/kg) is much higher than MMAF (Monomethylauristatin F) (1 mg/kg). cAC10-L1-MMAF4?has an MTD of 50 mg/kg in mice and 15 mg/kg in rats. The corresponding cAC10-L4-MMAF4?ADC was much less toxic, having MTDs in mice and rats of >150 mg/ kg and 90 mg/kg in rats, respectively.

Biological Activity

MMAF (Monomethylauristatin F) is a potent tubulin polymerization inhibitor and is used as a antitumor agent. MMAF (Monomethylauristatin F) is widely used as a cytotoxic component of antibody-drug conjugates (ADCs) such as vorsetuzumab mafodotin and SGN-CD19A.

in vitro

MMAF inhibits anaplastic large cell lymphoma Karpas 299, breast carcinoma H3396, renal cell carcinoma 786-O and Caki-1 cells with IC50s of 119, 105, 257 and 200 nM in vitro cytotoxicity assay.

Upstream product

• 159173-43-0 (2S,1'R,2'S)-N-(tert-butoxycarbonyl)-2-(1'-methoxy-2'-methyl-3'-butenyl)-pyrrolidine 
• 159173-40-7 (2S,1'R,2'S)-N-(tert-butoxycarbonyl)-2-(1'-hydroxy-2'-methyl-3'-butenyl)-pyrrolidine 
• 133645-49-5 (3R,4S,5S )-ethyl 4-((tert-butoxycarbonyl)amino)-3-hydroxy-5-methyl-heptanoate 
• 669074-47-9 methyl (S)-2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2-amino-N,3-dimethylbutanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanamido)-3-phenylpropanoate 
• 133565-39-6 (4S,5S)-ethyl 4-((tert-butoxycarbonyl)amino)-5-methyl-3-oxo-heptanoate 
• 13139-16-7 N-(tert-butyloxycarbonyl)-L-isoleucine 
• 149606-97-3 benzyl (2R,3R,2'S)-3-(N-tert-butoxycarbonyl-2'-pyrrolidinyl)-3-methoxy-2-methylpropanoate 
• 133565-38-5 (2R,3R)-3-[(2S)-1-[(tert-butoxy)carbonyl]pyrrolidin-2-yl]-3-hydroxy-2-methylpropanoic acid 
• 133645-50-8 (3R,4S,5S)-4-((tert-butoxycarbonyl)amino)-3-hydroxy-5-methyl-heptanoic acid 
• 180715-99-5 (4R,5S,2'R,3'R,2S)-3-[3'-(N-tert-butoxycarbonyl-2-pyrrolidinyl)-3'-methoxy-2'-methylpropanoyl]-4-methyl-5-phenyl-2-oxazolidinone 
• 133645-51-9 (4R,5S,2'R,3'R,2S)-3-[3'-(N-tert-butoxycarbonyl-2-pyrrolidinyl)-3-hydroxy-2'-methylpropanoyl]-4-methyl-5-phenyl-2-oxazolidinone 
• 69610-41-9 Boc-L-Pro-H 
• 69610-40-8 N-(tert-butoxycarbonyl)-L-prolinol 
• 15761-39-4 1-(tert-butoxycarbonyl)-L-proline 

Downstream Products

• 163768-50-1 ((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2-((S)-2-(dimethylamino)-3-methylbutyrylamino)-N,3-dimethylbutyrylamino)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropionyl)-L-phenylalanine 
• 1415329-56-4 C₂HF₃O₂*C₅₅H₉₆N₆O₁₃ 
• 1415329-57-5 C₅₁H₈₈N₆O₁₃*ClH 
• 1415328-86-7 C₅₂H₇₉N₇O₁₁ 
• 1415329-31-5 C₄₄H₇₇N₇O₉ 

Relevant academic research and scientific papers

EFFICIENT PREPARATION OF DOLASTATIN AND AURISTATIN ANALOGS THROUGH A COMMON INTERMEDIATE

Methods for making a dolastatin, auristatin or related compounds comprising the steps of providing a universal dolastatin core of Formula (I) reacting the C-terminal carboxylic acid group with an amine (A) to form an amide bond and reacting the N-terminal amine with a carboxylic acid (CA) to form an amide bond, wherein the steps can be performed in either order. Also provided are an isolated salt of the universal dolastatin core for use in preparation of dolastatins, auristatins and related compounds. Also provided are a number of intermediates and process steps which are useful for the preparation of high purity dolastatin core and high purity dolastatin and auristatin compounds.

NOVEL CONNECTED BODY AND USE THEREOF IN SPECIFIC CONJUGATION BETWEEN BIOMOLECULE AND DRUG

PROBLEM TO BE SOLVED: To provide: a method for producing a connected body; a method for using the connected body in the production of a uniform conjugate; and a method for applying the conjugate in the treatment of cancer, infectious diseases, and autoimmune diseases. SOLUTION: A novel connected body is provided that includes a 2,3-di-substituted succinic acid group or a 2-mono-substituted or 2,3-di-substituted fumaric acid or maleic acid (trans (E)- or cis (Z)-butenedioic acid) group for conjugating 2 or more compounds/cytotoxic agents per connected body with a cell-binding molecule by specifically bridge-linking to a pair of thiol on the cell-binding molecule. The connected body is exemplified by the following general formula. SELECTED DRAWING: None COPYRIGHT: (C)2021,JPOandINPIT

CONJUGATION LINKERS CONTAINING 2,3-DIAMINOSUCCINYL GROUP

Provided is a conjugate of a cytotoxic drug/molecule to a cell-binding molecule with a bis-linker (adual-linker) containing a 2, 3-diaminosuccinyl group. It also relates to preparation of the conjugate of a cytotoxic drug/molecule to a cell-binding molecule with the bis-linker, particularly when the drug having functional groups of amino, hydroxyl, diamino, amino-hydroxyl, dihydroxyl, carboxyl, hydrazine, aldehyde and thiol for conjugation with the bis-linker in a specific manner, as well as the therapeutic use of the conjugates.

CONJUGATION OF A CYTOTOXIC DRUG WITH BIS-LINKAGE

What provided is the conjugation of cytotoxic to a cell-binding molecule with a bis-linker(dual-linker) as shown in Formula (I). It provides bis-linkage methods of making a conjugate of a cytotoxic drug molecule to a cell-binding agent in a specific manner. It also relates to application of the conjugates for the treatment of a cancer, or an autoimmune disease, or an infectious disease.

CONJUGATION LINKERS, CELL BINDING MOLECULE-DRUG CONJUGATES CONTAINING THE LIKERS, METHODS OF MAKING AND USES SUCH CONJUGATES WITH THE LINKERS

The present invention relates to linkers having a group of propiolyl, substituted acryl (acryloyl), or disubstituted propanoyl, and using such linkers for the conjugation of compounds, in particular, cytotoxic agents to a cell-binding molecule.

Synthesis and biological activity evaluation of dolastatin 10 analogues with N-terminal modifications

We have described the synthesis of the two complex units (2R,3R,4S)-dolaproine (Dap) and (3R,4S,5S)-dolaisoleuine (Dil) of dolastatin 10 from natural amino acids. The stereoselective syntheses of N-Boc-Dap (4a) and N-Boc-(2S)-iso-Dap (4b) were performed by employing crotylation of N-Boc-L-prolinal as a key step. Barbier-type allylation of N-Boc-L-isoleucinal provided a mild and convenient approach for the synthesis of N-Boc-Dil (5a) and N-Boc-(3S)-iso-Dil (5b). Ten dolastatin 10 analogues have been designed and synthesized with N-terminal modifications based on the known compound monomethylauristatin F (MMAF, 3). In comparison with MMAF (3), four of the compounds showed enhanced potency against HCT 116 human colon cancer cells in?vitro.

SPECIFIC CONJUGATION LINKERS, SPECIFIC IMMUNOCONJUGATES THEREOF, METHODS OF MAKING AND USES SUCH CONJUGATES THEREOF

The present invention relates to novel linkers containing a 2,3-disubstituted succinic group, or 2-monosubstituted, or 2,3-disubstituted fumaric or maleic (trans (E)- or cis (Z)- butenedioic), or acetylenedicarboxyl group for conjugation of a cytotoxic agent, and/or one or more different functional molecules per linker to a cell-binding molecule, through bridge linking pairs of thiols on the cell-binding molecule specifically. The invention also relates to methods of making such linkers, and of using such linkers in making homogeneous conjugates, as well as of application of the conjugates in treatment of cancers, infections and autoimmune disorders.

NOVEL LINKERS AND THEIR USES IN SPECIFIC CONJUGATION OF DRUGS TO A BIOLOGICAL MOLECULE

The present invention relates to novel linkers containing a 2,3-disubstituted succinic group, or 2-monosubstituted, or 2,3-disubstituted fumaric or maleic (trans (E)- or cis (Z)- butenedioic) group for conjugation of two or more compounds/cytotoxic agents per linker to a cell-binding molecule, through bridge linking pairs of thiols on the cell-binding molecule specifically. The invention also relates to methods of making such linkers, and of using such linkers in making homogeneous conjugates, as well as of application of the conjugates in treatment of cancers, infections and autoimmune disorders.

PROSTATE-SPECIFIC MEMBRANE ANTIGEN ANTIBODY DRUG CONJUGATES

This invention relates to prostate-specific membrane antigen (PSMA) antibodies and antibody drug conjugates comprising at least one non-naturally-encoded amino acid. Disclosed herein are αPSMA antibodies with one or more non-naturally encoded amino acids and further disclosed are antibody drug conjugates wherein the αPSMA antibodies of the invention are conjugated to one or more toxins. Also disclosed herein are non-natural amino acid dolastatin analogs that are further modified post-translationally, methods for effecting such modifications, and methods for purifying such dolastatin analogs. Typically, the modified dolastatin analogs include at least one oxime, carbonyl, dicarbonyl, and/or hydroxylamine group. Further disclosed are methods for using such non-natural amino acid antibody drug conjugates, dolastatin analogs, and modified non-natural amino acid dolastatin analogs, including therapeutic, diagnostic, and other biotechnology uses.

COMPOSITIONS CONTAINING, METHODS INVOLVING, AND USES OF NON-NATURAL AMINO ACID LINKED DOLASTATIN DERIVATIVES

Disclosed herein are non-natural amino acids and dolastatin analogs that include at least one non-natural amino acid, and methods for making such non-natural amino acids and polypeptides. The dolastatin analogs can include a wide range of possible functionalities, but typically have at least one oxime, carbonyl, dicarbonyl, and/or hydroxylamine group. Also disclosed herein are non-natural amino acid dolastatin analogs that are further modified post-translationally, methods for effecting such modifications, and methods for purifying such dolastatin analogs. Typically, the modified dolastatin analogs include at least one oxime, carbonyl, dicarbonyl, and/or hydroxylamine group. Further disclosed are methods for using such non-natural amino acid dolastatin analogs and modified non-natural amino acid dolastatin analogs, including therapeutic, diagnostic, and other biotechnology use.