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Hydrophobic auristatin f compounds and conjugates thereof

A compound, hydrophobic technology, applied in the field of hydrophobic auristatin F compound and its related compounds and conjugates, can solve the problems of reducing the cell permeability of free drugs and not providing bystander activity

Pending Publication Date: 2020-11-24
思进股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this negative charge reduces the cell permeability of the free drug, such that the AF / MMAF conjugate, while providing potent activity against antigen-positive cells, provides limited or no bystander activity (Doronina, S.O. et al. "Novel Peptide linkers for highly potent antibody-auristatin conjugate"Bioconj.Chem.(2008)19:1960-1963)

Method used

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  • Hydrophobic auristatin f compounds and conjugates thereof
  • Hydrophobic auristatin f compounds and conjugates thereof
  • Hydrophobic auristatin f compounds and conjugates thereof

Examples

Experimental program
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Embodiment approach

[0275] A number of embodiments of the invention are described below, followed by a more detailed discussion of components, eg, groups, reactants and steps, suitable for use in the methods of the invention. Any selected embodiment of the components of the method may apply to each aspect of the invention as described herein or it may relate to a single aspect. Selected embodiments may be combined in any combination suitable to describe an auristatin ligand drug conjugate having a hydrophobic auristatin F drug unit, a drug linker compound, or an intermediate thereof.

[0276] 2.1 Hydrophobic auristatin drug unit

[0277] Hydrophobic auristatin drug units relate to hydrophobically modified auristatin F or auristatin F-type compounds in conjugated form, wherein the hydrophobicity of the parent compound has been increased so as to exhibit MDR when released as free drug + Dual activity with spectator. Ligand drug conjugates with such drug units would be directed against bystander...

Embodiment 1

[0777] Example 1. General procedure for lantern loading.

[0778] Series D trityl alcohol lamps (8 μmol / lamp) were treated with 0.5 mL of 10% (V / V) acetyl chloride in dry DCM for 3 hours at room temperature. The solution was filtered and the lamp was washed with dry DCM (3 x 3 mL) and used immediately without drying.

[0779] The lamp was treated with 0.5 mL of Fmoc-amino acid (0.14M, 70 μmol, 8.75 equiv) and DIPEA (0.5M, 260 μmol, 33 equiv) in DCM for 2 hours at room temperature. The solution was filtered and the lamp was washed with DCM (3 x 3 min) and DCM (3 x 3) min and dried in a desiccator under vacuum.

Embodiment 2

[0780] Example 2. General procedure for Fmoc deprotection

[0781] The lamp was treated with 0.5 mL of 20% (V / V) piperidine in DMF and shaken for 30 minutes. The solution was removed and the lamp was subjected to the same deprotection conditions. The solution was filtered and the lamp was washed with DCM (3 x 3 min) and DCM (3 x 3) min and dried in a desiccator under vacuum.

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PUM

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Abstract

Ligand Drug Conjugates of hydrophobically-modified auristatin F compounds that exhibit cytotoxic activities towards targeted cells, including abnormal cells such as cancer cells, that are MDR+ while also exhibiting bystander activities towards nearby cells having lower expression of the moeity targeted by the Conjugate.

Description

technical field [0001] The present invention relates to hydrophobic Auristatin F(AF) compounds and related compounds and conjugates thereof exhibiting MDR against a target antigen with a higher copy number + activity in cancer cells while exhibiting bystander activity against cancer cells with lower copy numbers or undetectable levels of the antigen. Background technique [0002] Traditional antibody auristatin drug conjugates exhibit targeting of MDR + Cancer cells may have bystander activity, but single-agent antibody auristatin drug conjugates exhibiting both desirable activities have not been reported. For MDR + The viability of the cells is considered desirable because the emergence of resistance to therapy is often associated with clonal expansion of cancer cells within the tumor, where surviving cells that persist after initial therapy have been selected on average to have higher copy numbers of Multidrug resistance transporter. Bystander activity is also a desira...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/02A61K47/64A61K47/68
CPCC07K5/0205A61K47/6851A61K47/6861A61K47/6867A61K47/6889A61P35/00A61K47/68031A61K47/6803A61K47/6881A61K47/65A61K47/64A61K31/74A61K38/02
Inventor S·O·多罗妮娜P·莫奎斯特
Owner 思进股份有限公司