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Heterotandem bicyclic peptide complexes

a bicyclic peptide and complex technology, applied in the field of heterotandem bicyclic peptide complexes, can solve the problem of reducing the conformational flexibility of the cyclic structure, and achieve the effect of preventing, suppressing or treating cancer

Active Publication Date: 2021-09-30
BICYCLETX LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about peptide complexes that can attach to both an immune cell and a cancer cell. These complexes can be used to prevent, suppress, or treat cancer.

Problems solved by technology

Good binding properties result from a relatively large interaction surface formed between the peptide and the target as well as the reduced conformational flexibility of the cyclic structures.

Method used

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  • Heterotandem bicyclic peptide complexes
  • Heterotandem bicyclic peptide complexes
  • Heterotandem bicyclic peptide complexes

Examples

Experimental program
Comparison scheme
Effect test

example 1

of Linkers

[0186]

[0187]A mixture of compound 1 (700.0 mg, 1.18 mmol, 1.0 eq), 3-azidopropan-1-amine (117.66 mg, 1.18 mmol, 1.0 eq), EDCI (270.4 mg, 1.41 mmol, 1.2 eq), HOBt (190.6 mg, 1.41 mmol, 1.2 eq) was dissolved in DCM (20 mL, pre-degassed and purged with N2 for 3 times), and then the mixture was stirred at 20-25° C. for 1 hr under N2 atmosphere. LC-MS showed compound 1 was consumed completely and one main peak with desired m / z (calculated MW: 677.33, observed m / z: 678.2 ([M+H]+)) was detected. The solvent was evaporated to produce compound 2 (600 mg, crude) was obtained as a white solid.

[0188]A mixture of compound 2 (600.0 mg, 885.3 μmol, 1.0 eq), N-ethylethanamine (1.29 g, 15.19 mmol, 1.50 mL, 17.2 eq) was dissolved in DCM (3 mL, pre-degassed and purged with N2 for 3 times), and then the mixture was stirred at 25-30° C. for 2 hr under N2 atmosphere. LC-MS showed compound 2 was consumed completely and one main peak with desired m / z (calculated MW: 455.51, observed m / z: 456.3 ([...

example 2

of EphA2 / CD137 Binding Heterotandem Bicyclic Peptides

[0212]

Procedure for Preparation of BCY9172-PEG12-N3

[0213]

[0214]BCY9172 (520 mg, 248.16 μmol, 1 eq) and compound 1 (370 mg, 499.47 μmol, 2.01 eq), were dissolved in in DMF (5 mL) was added DIEA (48.11 mg, 372.24 μmol, 64.84 μL, 1.5 eq) and then the mixture was stirred at 30° C. for 12 hr. LC-MS showed BCY9172 was consumed completely and one main peak with desired m / z (calculated MW: 2721.12 observed m / z: 1360.9 ([M / 2+H]+)) was detected. The reaction mixture was purified by prep-HPLC (TFA condition) and compound 2 (284 mg, 101.10 μmol, 40.74% yield, 96.87% purity) was obtained as a white solid.

Procedure for Preparation of BCY9173

[0215]This reaction was performed in two independent containers in parallel. For one container, Compound 2 (100 mg, 36.75 μmol, 1.0 eq) and BCY6169 (120 mg, 36.78 μmol, 1.0 eq) were first dissolved in 10 mL of t-BuOH / H2O (1:1), and then CuSO4 (0.4 M, 91.9 μL, 1.0 eq), VcNa (0.4 M, 183.8 μL, 2.0 eq) and THPTA...

example 3

of Nectin-4 / CD137 Binding Heterotandem Bicyclic Peptides

[0300]

General Procedure for Preparation of BCY8846

[0301]

[0302]To a solution of BCY8234 (a peptide identical to BCY8846 except for the absence of a PYA moiety; 300 mg, 102 μmol, 1.0 eq) in DMA (3 mL) was added DIEA (52.5 mg, 406 μmol, 70.8 μL, 4.0 eq) with stirring for 10 min. Then (2,5-dioxopyrrolidin-1-yl) pent-4-ynoate (25.8 mg, 132 μmol, 1.3 eq) was added thereto and the mixture was further stirred at 20° C. for additional 16 hr. LC-MS showed BCY8234 was consumed completely and one main peak with desired m / z (calculated MW: 3034.43, observed m / z: 1011.8 ([M / 3+H]+), 1517.0 ([M / 2+H]+)) was detected. The reaction mixture was purified by prep-HPLC (neutral condition) to give compound BCY8846 (290 mg, 95.6 μmol, 94.1% yield) as a white solid.

General Procedure for Preparation of BCY8854

[0303]

[0304]To a solution of BCY8846 (234 mg, 77.1 μmol, 1.0 eq) in DMF (5 mL) was added BCY7859 (which may be prepared as described in BCY7985; 22...

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Abstract

The present invention relates to heterotandem bicyclic peptide complexes which comprise a first peptide ligand, which binds to a component present on an immune cell, conjugated via a linker to a second peptide ligand, which binds to a component present on a cancer cell. The invention also relates to the use of said heterotandem bicyclic peptide complexes in preventing, suppressing or treating cancer.

Description

FIELD OF THE INVENTION[0001]The present invention relates to heterotandem bicyclic peptide complexes which comprise a first peptide ligand, which binds to a component present on an immune cell, conjugated via a linker to a second peptide ligand, which binds to a component present on a cancer cell. The invention also relates to the use of said heterotandem bicyclic peptide complexes in preventing, suppressing or treating cancer.BACKGROUND OF THE INVENTION[0002]Cyclic peptides are able to bind with high affinity and target specificity to protein targets and hence are an attractive molecule class for the development of therapeutics. In fact, several cyclic peptides are already successfully used in the clinic, as for example the antibacterial peptide vancomycin, the immunosuppressant drug cyclosporine or the anti-cancer drug octreotide (Driggers et al. (2008), Nat Rev Drug Discov 7(7), 608-24). Good binding properties result from a relatively large interaction surface formed between the...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/12C07K7/08C07K7/06C07K7/50A61P35/00
CPCA61K38/12C07K7/08A61P35/00C07K7/50C07K7/06C07K14/001C07K14/70503C07K14/70578C07K14/715C07K17/08A61K38/00C07K14/70575C07K14/705C07K14/47C07K14/78C07K2319/00
Inventor KEEN, NICHOLASMCDONNELL, KEVINPARK, PETERUPADHYAYA, PUNIT
Owner BICYCLETX LTD
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