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Bicyclic peptide ligands with detectable moieties and uses thereof

A single-ring, compound technology, applied in the field of peptides, can solve problems such as unsatisfied

Pending Publication Date: 2020-04-17
BICYCLERD LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Therefore, there remains a high unmet need in the development of drugs that selectively bind transmembrane proteins such as CAIX, MT1-MMP, PSMA, CD38, EphA2 or αvβ3 for diagnosis, imaging and treatment of cancer

Method used

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  • Bicyclic peptide ligands with detectable moieties and uses thereof
  • Bicyclic peptide ligands with detectable moieties and uses thereof
  • Bicyclic peptide ligands with detectable moieties and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0538] Example 1: Peptide Synthesis - Molecular Scaffold Reagents with Leaving Groups

[0539] Peptide synthesis was performed based on Fmoc chemistry using a Symphony peptide synthesizer manufactured by Peptide Instruments and a Syro II synthesizer manufactured by MultiSynTech. Standard Fmoc amino acids (Sigma, Merck) with appropriate side chain protecting groups were employed: where applicable, standard coupling conditions were used in each case, followed by deprotection using standard methods . The peptides were purified using HPLC, and after isolation, they were modified with a molecular scaffold reagent with a leaving group. For this purpose, linear peptides were treated with H 2 O was diluted to about 35 mL, about 500 μL of acetonitrile containing 100 mM molecular scaffold reagent was added, and 5 mL of 1M NH 4 HCO 3 H 2 O initiates the reaction. The reaction was carried out at room temperature for about 30-60 minutes and was lyophilized once the reaction was compl...

example 2

[0540] Example 2: Peptide Synthesis - Molecular Scaffold Reagents Containing Michael Acceptors

[0541] Alternatively, the peptides are purified using HPLC, and after isolation, they are modified with molecular scaffolding reagents containing Michael acceptors. For this, use 50:50MeCN:H 2 O Dilute the linear peptide up to about 35 mL, add about 500 μL of acetonitrile containing 100 mM Michael acceptor-containing molecular scaffold reagent, and wash with 5 mL of 1M NH 4 HCO 3 H 2 O initiates the reaction. The reaction was carried out at room temperature for about 30-60 minutes and was lyophilized once the reaction was complete (as judged by MALDI). Once complete, dissolve 1 mL of 1 M L-cysteine ​​hydrochloride monohydrate (Sigma) in HO at room temperature 2 O was added to the reaction for approximately 60 min to quench any excess molecular scaffold reagents containing Michael acceptors.

[0542] After lyophilization, the modified peptide was purified as described above wh...

example 3

[0544] Example 3: Conjugation of bicyclic peptides to DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)

[0545] 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) is a complexing agent that can be conjugated to a bicyclic ring to obtain a construct that The body is using radioactive isotopes (i.e., Lu 3+ ) or MRI contrast agent (ie, Gd 3+ ) labeled for biodistribution studies in animal models. Commercially available DOTA N-succinimide esters are coupled to the amino group of the bicyclic peptide, usually the N-terminal amino group.

[0546]

[0547] name CAS number mw DOTA N-succinimide ester 170908-81-3 761.48

[0548] Materials and methods

[0549] equipment

[0550] LCMS

[0551] MALDI mass spectrometer

[0552] Solvents and compounds and consumables

[0553] Dry dimethyl sulfoxide (DMSO)

[0554] DOTA N-succinimide ester

[0555] N,N-Diisopropylethylamine (DIPEA)

[0556] 100mM Tris(hydroxymethyl)aminometha...

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Abstract

The present invention provides compounds, compositions thereof and methods of using the same.

Description

[0001] sequence listing [0002] This application contains a Sequence Listing that has been filed electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on June 25, 2018, is named 392664-004WO(160781)_SL.txt and is 3,997 bytes in size. technical field [0003] The present invention relates to polypeptides that are covalently bound to a molecular scaffold such that two or more peptide loops are opposed between attachment points of the scaffold and further linked to a detectable moiety. In particular, the present invention describes bicyclic peptide ligands that can be used to selectively deliver attached detectable moieties to cancer cells. The present invention also describes peptides which are carbonic anhydrase IX (CAIX), membrane type 1 metalloprotease (MT1-MMP), prostate-specific membrane antigen (PSMA), cluster of differentiation 38 (CD38), Eph receptor tyrosine High-affinity binder for amino acid kinase A2 (Eph...

Claims

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Application Information

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IPC IPC(8): C07K7/08A61K51/00
CPCA61K49/0032A61K49/0043A61K49/0056A61K51/088C07K7/08C07K14/001C07K7/56
Inventor G·贝内特D·P·托伊费尔
Owner BICYCLERD LTD
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