Novel BH3 analogue targeted to Bcl-2 family anti-apoptotic protein and application of novel BH3 analogue

An anti-apoptotic protein and analog technology, applied in the field of medicinal chemistry, can solve problems such as inability to antagonize Mcl-1 protein, and achieve the effects of simple structure and low synthesis cost.

Inactive Publication Date: 2017-04-19
MARINE BIOMEDICAL RES INST OF QINGDAO CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Clinical studies have shown that ABT-263, like ABT-737, cannot antagonize Mcl-1 protein, and its single-ag

Method used

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  • Novel BH3 analogue targeted to Bcl-2 family anti-apoptotic protein and application of novel BH3 analogue
  • Novel BH3 analogue targeted to Bcl-2 family anti-apoptotic protein and application of novel BH3 analogue
  • Novel BH3 analogue targeted to Bcl-2 family anti-apoptotic protein and application of novel BH3 analogue

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Embodiment 1: the preparation of compound SM-1

[0029] (1) Resin activation: Weigh 500mg Rink Amide-AM resin, wash 4 times with DCM, add 5ml DCM to swell and activate for 3 hours, wash 4 times with DMF, add 20% piperidine DMF to remove Fmoc protecting group for 20min, wash 4 times with 5ml DMF times, washed 4 times with 5ml DCM, and tested with Kaiser's reagent.

[0030] (2) Connect Ala: wash with DMF for 3 times, add 3 times equivalents of Fmoc-Ala-OH, HBTU, HOBt and 6 times equivalents of DIEA respectively, dissolve in 10ml DMF, stir at room temperature for 2 hours, wash with DMF 4 times, add Remove the Fmoc protecting group with 20% piperidine in DMF for 20 minutes, wash 4 times with 5ml DMF and 4 times with 5ml DCM, and detect with Kaiser's reagent.

[0031] (3) Asn connection: wash with DMF for 3 times, add 3 times equivalents of Fmoc-Asn(Trt)-OH, HBTU, HOBt and 6 times equivalents of DIEA respectively, dissolve in 10ml DMF, stir at room temperature for 2 hours, ...

Embodiment 2

[0052] Embodiment 2: Confirmation of the secondary structure of the compound of the present invention

[0053] In this example, circular dichroism chromatography was used to study the secondary structure of the compound of the present invention. The circular dichroism spectrum of the compound is as figure 1 shown. Circular dichroism is a special absorption spectrum, which obtains the secondary structure of biomacromolecules by measuring the circular dichroism spectrum of biomacromolecules. In the ultraviolet region of circular dichroism spectrum (190-240nm), the main chromophore is the peptide chain, and the CD spectrum in this wavelength range contains the conformation information of the main chain of biological macromolecules. The CD spectrum of α-helical conformation has negative peaks at 222nm and 208nm, and a positive peak near 190nm. The CD spectrum of the β-sheet conformation has a negative peak at 217-218nm and a strong positive peak at 195-198nm. The CD spectrum o...

Embodiment 3

[0055] Embodiment 3: Compounds of the present invention interact with target protein molecules

[0056] The present invention adopts The HT biomolecular interaction analysis system measures the affinity activity between the BH3 analogue and the target protein. The biomolecular interaction system is a surface plasmon resonance imaging (SPRi) system based on microarray technology. function without labeling. In order to understand the specificity of molecular binding, accurately calculate the kinetic data of molecular binding, and understand the binding process of biomolecules. Through PLEXERA SPR Date Analysis Module (DAM) analysis software for data analysis and fitting, kinetic data such as binding curves, binding, dissociation, and equilibrium dissociation constants can be obtained.

[0057] Specific operation method:

[0058] The chip surface was mixed with 0.4M EDC (N-ethyl-N’-dimethylaminopropylcarbodiimide) and 0.1M NHS (N-hydroxysuccinimide) 1:1 to activate the chip...

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Abstract

The invention discloses a novel BH3 analogue targeted to Bcl-2 family anti-apoptotic protein and application of the novel BH3 analogue. The structural general formula of the BH3 analogue is as shown in the general formula A (the general formula A can be found in specification). A thought and method of peptidomimetics is adopted, the structure of a natural BH3 peptide fragment is simplified or modified, and the novel BH3 analogue is obtained. It is proved by experiments that the compound as shown in the general formula A and the Bcl-2 family anti-apoptotic protein represent excellent binding activity on the aspect of the molecular level; and it is shown by in-vitro carcinoma cell growth inhibition experiments that the compound has a certain in-vitro growth inhibition function on the human chronic myeloid leukemia cell K562, the human promyelocytic lenukemia cell HL-60 and the human tissue cell lymphoma cell U937. It is prompted by research results that the compound can be used as a candidate drug for preventing or treating related diseases caused by expression abnormality of anti-apoptotic protein in the Bcl-2 family protein.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and specifically relates to a class of novel BH3 analogs targeting Bcl-2 family anti-apoptotic proteins, which have a simpler structure and better target protein binding activity than natural BH3, and applications thereof. Background technique [0002] Apoptosis is a programmed cell suicide death process triggered by internal and external stimuli. Normal cells operate according to the "program" of life, and must undergo apoptosis after a certain period of time. This apoptosis is an autonomous cell death mode controlled by a series of apoptosis factors in order to maintain the balance of the body and the stability of the internal environment. This process is crucial for the development of multicellular animals, and dysregulation of normal apoptosis can lead to abnormal body morphology and a variety of diseases, such as cancer, neurodegenerative diseases and autoimmune diseases. Tumor ...

Claims

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Application Information

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IPC IPC(8): C07K14/47A61K38/17A61K38/08A61K38/10A61P35/00A61P37/00A61P35/02
CPCC07K14/4747A61K38/00
Inventor 王树林张传亮刘珊柳晓春高江明蔡兵管华诗
Owner MARINE BIOMEDICAL RES INST OF QINGDAO CO LTD
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