Application of malt1 targeting inhibitor in the preparation of malt1-dependent tumor therapy drugs

A dependence and tumor technology, applied in the field of biomedicine, can solve problems such as off-target effects, low cell permeability, and limited development and utilization

Active Publication Date: 2020-03-20
SHANGHAI INST OF BIOLOGICAL SCI CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although some inhibitors have been discovered, their own shortcomings limit the further development and utilization of these inhibitors as clinical drugs
Z-VRPR-FMK is a polypeptide inhibitor that can specifically and irreversibly inhibit the activity of MALT1 (F.Rebeaud et al., The proteolytic activity of the paracaspase MALT1 is key in Tcell activation., Nat.Immunol., vol.9 , no.3, pp.272-281, 2008), but its cell permeability is not high; phenothiazine derivatives are allosteric inhibitors of MALT1, but because they are also dopamine receptor antagonists, so Side effects such as off-target effects may occur; MI-2 is an important small molecule inhibitor of MALT1 discovered in recent years, which can irreversibly inhibit enzyme activity (L.Fontan et al., MALT1 small molecule inhibitors specifically suppress ABC-DLBCL in vitro and in vivo., Cancer Cell, vol.22, no.6, pp.812-24, 2012), but due to its solubility and stability, it still needs further optimization; and β-lapachone can inhibit The activity of MALT1, but its half-growth inhibitory concentration (IG50) to ABC-DLBCL cells is 1-10uM, and the killing or inhibition needs to be further optimized and improved (S.M.Lim et al., Identification of β-Lapachone Analogs as Novel MALT1 Inhibitors To Treat an Aggressive Subtype of Diffuse Large B-Cell Lymphoma, J.Med.Chem., p.acs.jmedchem.5b01415, 2015)

Method used

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  • Application of malt1 targeting inhibitor in the preparation of malt1-dependent tumor therapy drugs
  • Application of malt1 targeting inhibitor in the preparation of malt1-dependent tumor therapy drugs
  • Application of malt1 targeting inhibitor in the preparation of malt1-dependent tumor therapy drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Embodiment 1, LZ-MALT1 protein expression and purification

[0047] Because the full-length MALT1 and its caspase-like domain (340-789 amino acids) exist as monomers in physiological solution, the enzymatic cleavage activity is low, and MALT1 needs to form a dimer to better exert the enzymatic cleavage activity. After analysis and research, the inventors fused the caspase-like domain (340-789) fragment of MALT1 with the leucine zipper dimer fragment to construct an in vitro recombinant protein of LZ-MALT1.

[0048] The amino acid sequence of MALT1 (340-789) is as follows (SEQ ID NO: 1):

[0049] AKDKVALLIGNMNYREHPKLKAPLVDVYELTNLLRQLDFKVVSLLDLTEYEMRNAVDEFLLLLDKGVYGLLYYAGHGYENFGNSFMVPVDAPNPYRSENCLCVQNILKLMQEKETGLNVFLLDMCRKRNDYDDTIPILDALKVTANIVFGYATCQGAEAFEIQHSGLANGIFMKFLKDRLLEDKKITVLLDEVAEDMGKCHLTKGKQALEIRSSLSEKRALTDPIQGTEYSAESLVRNLQWAKAHELPESMCLKFDCGVQIQLGFAAEFSNVMIIYTSIVYKPPEIIMCDAYVTDFPLDLDIDPKDANKGTPEETGSYLVSKDLPKHCLYTRLSSLQKLKEHLVFTVCLSYQYSGLEDTVEDKQEVNVGKPLIAKLDMHRG...

Embodiment 2

[0056] Example 2, High-throughput screening of LZ-MALT1-specific small molecule inhibitors

[0057]The screening system established by the present inventors includes LZ-MALT1 and Ac-LVSR-AMC, wherein Ac-LVSR-AMC is the substrate of MALT1, MALT1 can recognize and cut the LVSR site, and the released AMC group can emit Fluorescence, so the enzymatic activity of MALT1 can be characterized by the detected fluorescence value. For determining the optimal high-throughput screening reaction conditions, the inventors set a series of LZ-MALT1 concentrations (25nM, 50nM, 100nM, 200nM, etc.) and substrate concentrations (62.5uM, 125uM, 250uM, etc.), and did two Dimensional orthogonal experiment, detect and record the fluorescence value every 30 seconds, the results are as follows figure 2 As shown, the fluorescence value has a linear relationship with time. As the substrate concentration increases, the reaction signal increases, and as the enzyme concentration increases, the reaction sig...

Embodiment 3

[0068] Embodiment 3, the effect verification of compound

[0069] For the small molecular compounds screened in Example 2, the effects of these compounds were verified by dose-response experiments, with the half inhibitory concentration (IC50) being less than 20 μM and having a good dose-response curve as the standard.

[0070] From these compounds, a small molecular compound with strong inhibitory effect, S-type dose-response curve, and IC50 less than 1nM was obtained as a MALT1 inhibitor, such as image 3 and Table 2.

[0071] Table 2

[0072]

[0073] The compounds in Table 2 can effectively inhibit the activity of MALT1 in vitro, are effective MALT1 inhibitors, and can be used as targeted drugs for the clinical treatment of ABC-DLBCL.

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Abstract

The invention relates to application of an MALT1 targeting inhibitor to preparation of an MALT1-dependent tumor treating medicine. The inventor screens out a compound with an MALT1 inhibiting function from a large number of compounds, so that a potential medicine is provided for clinically treating MALT1-dependent tumors such as diffuse large B cell lymphoma.

Description

technical field [0001] The invention belongs to the field of biomedicine, and more specifically, the invention relates to the application of MALT1 targeting inhibitors in the preparation of MALT1-dependent tumor treatment drugs. Background technique [0002] Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma, which can be divided into three subtypes according to its gene expression profile: germinal center B cell type ( Germinal center B cell like DLBCL (GCB-DLBCL), activated B cell like DLBCL (ABC-DLBCL) and primary mediastinal B cell lymphoma (PMBL). Among them, ABC-DLBCL has the highest degree of malignancy and is strongly resistant to existing immunochemotherapy. After classic R-CHOP treatment, the five-year survival rate of GCB-DLBCL can reach 76%, while the five-year survival rate of ABC-DLBCL is only about 30%. Therefore, it is important to find effective drugs and treatments for ABC-DLBCL Clinical problems that need to be solved urgently....

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/235A61P35/00
CPCA61K31/235
Inventor 杨成华孙晨霞闫文芬
Owner SHANGHAI INST OF BIOLOGICAL SCI CHINESE ACAD OF SCI
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