Small-molecule inhibitor targeting PD-L1 gene and application of small-molecule inhibitor

A small molecule inhibitor, PD-L1 technology, applied in the direction of anti-tumor drugs, drug combinations, etc., can solve the problems of less than 30% overall response rate, obvious differential response of patients, and difficult transportation, so as to inhibit tumor immune escape, Inhibit cell migration and enhance the killing effect

Active Publication Date: 2021-07-13
杭州庆正鸿科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these antibodies also have some problems that cannot be solved at present, such as: obvious differences in response to patients, the overall response rate is less than 30%, the immunogenicity of the antibody, it can only be injected and it is difficult to take orally, it is difficult to store and transport, and the cost is high, etc.
Other small-molecule compounds for this target research have also been reported recently, but they have not been used in clinical practice. Therefore, the discovery of small-molecule PD-L1 gene inhibitors is promising but also a great challenge.

Method used

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  • Small-molecule inhibitor targeting PD-L1 gene and application of small-molecule inhibitor
  • Small-molecule inhibitor targeting PD-L1 gene and application of small-molecule inhibitor
  • Small-molecule inhibitor targeting PD-L1 gene and application of small-molecule inhibitor

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Embodiment 1: the preparation of polyamide 1

[0033] The abbreviations of the starting materials and reagents used are listed in Table 1.

[0034] Table 1: Reagents and their abbreviations used in solid-phase synthesis reactions

[0035]

[0036] The synthesis steps are as follows:

[0037] 1) Activation: Weigh image 3Fmoc protection β-alanine-Clear resin (SPS-1, 1.00g, 0.4mmol, Peptides International) as shown in formula (9) joins in the solid-phase reaction tube of solid-phase reaction device, logical nitrogen protection, again Add 5mL of DMF to fully bubble nitrogen for 30min to activate the resin;

[0038] 2) Deprotection: first prepare 3 mL of 20% (v / v) piperidine / DMF (both piperidine and DMF are treated anhydrous solvents), and add it to the solid-phase reaction tube of step 1) under nitrogen protection, Fully bubbling reaction for 15 minutes, remove the amino protecting group on β-alanine, remove the solvent in the reaction tube, rinse twice with 3mL anh...

Embodiment 2

[0070] Embodiment 2: the preparation of polyamide 2

[0071] The synthesis steps are similar to the synthesis of polyamide 1, and the specific steps are as follows:

[0072] 1) Activation: Weigh image 3 Fmoc protection β-alanine-Clear resin (SPS-1, 1.00g, 0.4mmol, Peptides International) as shown in formula (9) joins in the solid-phase reaction tube of solid-phase reaction device, logical nitrogen protection, again Add 5mL of DMF to fully bubble nitrogen for 30min to activate the resin;

[0073] 2) Deprotection: first prepare 3 mL of 20% (v / v) piperidine / DMF (both piperidine and DMF are treated anhydrous solvents), and add it to the solid-phase reaction tube of step 1) under nitrogen protection, Fully bubbling reaction for 15 minutes, remove the amino protecting group on β-alanine, remove the solvent in the reaction tube, rinse twice with 3mL anhydrous dichloromethane, rinse once with 2mL anhydrous DMF, each time Drain the solvent after rinsing;

[0074] 3) Coupling: Weig...

Embodiment 3

[0097] Embodiment 3: Preparation of mismatched polyamide

[0098] The synthesis steps are similar to the synthesis of polyamide 1, and the specific steps are as follows:

[0099] 1) Activation: Weigh image 3 Fmoc protection β-alanine-Clear resin (SPS-1, 1.00g, 0.4mmol, Peptides International) as shown in formula (9) joins in the solid-phase reaction tube of solid-phase reaction device, logical nitrogen protection, again Add 5mL of DMF to fully bubble nitrogen for 30min to activate the resin;

[0100] 2) Deprotection: first prepare 3 mL of 20% (v / v) piperidine / DMF (both piperidine and DMF are treated anhydrous solvents), and add it to the solid-phase reaction tube of step 1) under nitrogen protection, Fully bubbling reaction for 15 minutes, remove the amino protecting group on β-alanine, remove the solvent in the reaction tube, rinse twice with 3mL anhydrous dichloromethane, rinse once with 2mL anhydrous DMF, each time Drain the solvent after rinsing;

[0101] 3) Coupling:...

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Abstract

The invention discloses a PD-L1 gene targeting small-molecule inhibitor and application thereof, wherein the PD-L1 gene targeting small-molecule inhibitor is a pyrrole-imidazole polyamide compound, and can competitively bind to a binding sequence of STAT3 protein in a promoter region of a PD-L1 gene to influence transcription and translation of the PD-L1 gene. According to the invention, the polyamide 1 and the polyamide 2 have good anti-tumor activity, and tumor cell apoptosis is finally caused through immune and non-immune ways.

Description

technical field [0001] The invention relates to a small molecule inhibitor targeting PD-L1 gene and application thereof. Background technique [0002] In the 20th century, when people were studying fusimycin and distamycin, they discovered that a class of small molecular compounds could specifically recognize DNA molecules and bind at the minor groove of double-stranded DNA molecules. Inspired by these two small molecular compounds, the research team of Perter Dervan at Caltech first designed and synthesized a five-membered aromatic ring composed of amino acid, N-methylpyrrole (Py) and N-methylimidazole (Im) via an amide bond. The molecules formed by the connection are commonly called: pyrrole-imidazole polyamide (Py-Impolyamide). They can specifically recognize and bind DNA base sequences, and have good cell membrane permeability. The PerterDervan research group revealed the specific rules for the recognition of DNA sequences by pyrrole-imidazole polyamides, that is, Im / P...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G69/08C08G69/04A61P35/00
CPCC08G69/08C08G69/04A61P35/00
Inventor 张文吴艳玲杉山弘周康毛慧娟王明
Owner 杭州庆正鸿科技有限公司
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