CN107296807A - Application of the MALT1 targeted inhibitions thing in MALT1 dependent tumors medicines are prepared - Google Patents
Application of the MALT1 targeted inhibitions thing in MALT1 dependent tumors medicines are prepared Download PDFInfo
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Abstract
The present invention relates to application of the MALT1 targeted inhibitions thing in MALT1 dependent tumors medicines are prepared.The present inventor screens one from substantial amounts of compound has suppression MALT1 functional compounds, and potential medicine is provided for clinical treatment MALT1 dependent tumors such as diffusivity large B cell lymphoid tumor.
Description
Technical field
The invention belongs to biomedicine field, more particularly it relates to MALT1 targeted inhibition things
Application in MALT1 dependent tumors medicines are prepared.
Background technology
Diffusivity large B cell lymphoid tumor (Diffuse large B cell lymphoma, DLBCL) is most normal
The NHL seen, three hypotypes can be classified as according to the difference of its gene expression atlas：It is raw
Send out center B cell type (Germinal center B cell like DLBCL, GCB-DLBCL), activated b
Cellular type (Activated B cell like DLBCL, ABC-DLBCL) and primary vertical diaphragm B cell type
(Primary mediastinal B cell lymphoma, PMBL).Wherein ABC-DLBCL pernicious journey
Highest is spent, there is strong drug resistance to existing immunochemotherapy.After classical R-CHOP treatments,
GCB-DLBCL five-year survival rate can reach 76%, and ABC-DLBCL five-year survival rate only has
30% or so, therefore, the medicine and treatment method that searching can effectively treat ABC-DLBCL are clinically
Urgent problem.Research shows that ABC-DLBCL key character is NF- κ B signal paths
Sustained activation, because the activation of the signal path has the propagation for promoting B cell and survival in B cell,
Suppress the effect of apoptosis, the activation of its continuation is probably the weight for causing ABC-DLBCL hypotype prognosis poor
Reason is wanted, the continuation activation for pointing out to suppress NF- κ B signals is the key for treating ABC-DLBCL.But
Be, due to NF- κ B in each tissue and organ wide expression, be the transcription with extensive important function because
Son, it is combined after being activated into nucleus with target dna, participates in the transcription of regulation lots of genes
And expression, serious toxic side effect will be caused by directly suppressing NF- κ B, therefore NF- κ B are in itself and uncomfortable
Cooperate as drug therapy related target.
Research shows, is made up of CARMA1 (also referred to as CARD11), BCL10 and MALT1
CBM compounds mediated in lymphocyte NF- κ B activation have important effect.
Usually visible CARMA1, the mutation of BCL10 and MALT1 genes in ABC-DLBCL tumour cells
Or indexing, cause CARMA1, BCL10 and MALT1 increased activity or in continuous activation
State, and then cause NF- κ B overactivity and the generation of tumour.RNA interference experiments show
Survival and propagation of the CBM compounds for ABC-DLBCL cells are extremely important, suppress CBM table
Danone optionally kills ABC-DLBCL cells (V.N.Ngo etc., A loss-of-function RNA
interference screen for molecular targets in cancer.,Nature,vol.441,no.7089,
pp.106–110,2006).It will be treatment ABC-DLBCL optionally, therefore to hinder CBM signals
A very promising strategy.In CBM compounds, CARMA1 and BCL10 are supports
Albumen, without enzymatic activity, and MALT1 is a kind of similar caspase protease, can be by it
The NF- κ B such as digestion activity inactivation A20 and CYLD negative regulatory factor, so as to promote NF- κ B work
Change (I.S.Afonina etc., MALT1-a universal soldier:multiple strategies to ensure
NF-κB activation and target gene expression.,FEBS J.,vol.282,pp.1-12,
2015).In ABC-DLBCL, MALT1 usually in persistent activation state and causes NF- κ B
The sustained activation of signal path, growth factor can be reduced and swollen by specifically suppressing MALT1 activity
The generation of knurl repressor, thus cause ABC-DLBCL cell deaths and growth inhibition (U.Ferch etc.,
Inhibition of MALT1 protease activity is selectively toxic for activated B
cell-like diffuse large B cell lymphoma cells.,J.Exp.Med.,vol.206,no.11,pp.
2313-2320,2009；S.Hailfinger etc., Essential role of MALT1 protease activity in
Activated B cell-like diffuse large B-cell lymphoma., Proc.Natl.Acad.Sci.U.S.
A.,vol.106,no.47,pp.19946-19951,2009).Importantly, MALT1 knock-out mices
There is no special phenotype, grievous injury (A.A.Ruefli-Brasse etc. physiologically is not caused to mouse
Regulation of NF-κB-Dependent Lymphocyte Activation and Development by
Paracaspase, " Science (80-.), vol.302, no.5650, pp.1581-1584,2003), imply that
Serious side effect can't be produced to patient by specifically suppressing MALT1.Therefore, MALT1 is to control
Treat the ABC-DLBCL potential safely and effectively drug target of very tool.
In recent years, find MALT1 targeted inhibition agent turns into research to treat ABC-DLBCL
Focus.Although there is some inhibitor to have been observed that, some shortcomings themselves existed limit this
A little inhibitor as clinical medicine further exploitation.Z-VRPR-FMK is that a kind of polypeptide suppresses
Agent, can specifically, irreversibly suppress MALT1 activity (F.Rebeaud etc., The proteolytic
Activity of the paracaspase MALT1 is key in T cell activation., Nat.Immunol.,
Vol.9, no.3, pp.272-281,2008), but its cell permeability is not high；The derivative of phenthazine
It is MALT1 allosteric inhibitor, but is due to it while being also the antagonist of dopamine receptor, therefore
The side effects such as effect of missing the target may be produced；MI-2 is an important MALT1 of discovered in recent years
Micromolecular inhibitor, being capable of irreversibly inhibitory enzyme activity (L.Fontan etc., MALT1 small
Molecule inhibitors specifically suppress ABC-DLBCL in vitro and in vivo.,
Cancer Cell, vol.22, no.6, pp.812-24,2012), but be due to its dissolubility and stability
The problem of, it is still desirable to further optimization；Although and β-lapachol can suppress MALT1's in vitro
Activity, but its half growth inhibition ratio concentration (IG50) to ABC-DLBCL cells is killed in 1-10uM
Wound or inhibitory action need to be optimized and improved (S.M.Lim etc., 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).
Therefore, novel MALT1 inhibitor is found for targeted therapy malignant tumour ABC-DLBCL
It is significant.
The content of the invention
Swollen it is an object of the invention to provide MALT1 targeted inhibitions thing in preparation MALT1 activity dependent enzymes
Application in knurl such as diffusivity large b-cell lymphoma treating medicine.
Prepared in the first aspect of the present invention there is provided compound or its pharmaceutically acceptable salt or precursor
Purposes in MALT1 inhibitor；Wherein, described compound is：
In another preference, described MALT1 inhibitor prevention or treatment MALT1 activity dependent enzymes
Tumour.
In another preference, described MALT1 activity dependent enzymes tumours include but is not limited to activated b
Cellular type (ABC-DLBCL) diffusivity large B cell lymphoid tumor.
In another preference, described compound suppresses CARMA1 by suppressing MALT1
Or the CBM compounds of its family protein, BCL10 and MALT1 compositions, so as to play prevention or control
Treatment is acted on.
In another preference, described CARMA1 family protein includes but is not limited to：
CARMA2, CARMA3, CARD9.
There is provided a kind of method for preparing MALT1 inhibitor, methods described in another aspect of this invention
Including：Compound is mixed with pharmaceutically acceptable carrier, MALT1 inhibitor is obtained；Described
The structural formula of compound is：
The other side of the present invention, due to this disclosure, is aobvious to those skilled in the art
And be clear to.
Brief description of the drawings
Fig. 1, LZ-MALT1 cementing fruits of the SDS-PAGE of gel permeation chromatography peak shape figure and peak product
Figure.
The inhibition of Fig. 2, positive control Z-VRPR-FMK to MALT1.
Fig. 3, micromolecular compound WX28 suppress MALT1 dose-response curve.
The growth inhibition effect of Fig. 4, WX28 to DLBCL cells.
Embodiment
The present inventor is by in-depth study and screening, and one is screened from substantial amounts of compound has suppression
MALT1 functional compounds processed, described compound inhibitory action is notable.The present invention is clinical treatment
MALT1 dependent tumors such as diffusivity large B cell lymphoid tumor provides potential medicine.
Compound and application thereof
This area is it has been determined that MALT1 is a kind of similar Caspase enzyme, and its proteolytic cleavage is active
Tumour to malignant tumour diffusivity large B cell lymphoid tumor, particularly ABC-DLBCL type lymthomas is thin
Born of the same parents' survival is extremely important, and suppressing its activity can efficiently and selectively suppress and kill ABC-DLBCL
Tumour cell.Hence, it can be determined that, suppressing MALT1 material (MALT1 inhibitor) can prevent
Or treatment diffusivity large B cell lymphoid tumor, particularly ABC-DLBCL type lymthomas.
The present inventor's early stage establishes the method that can quickly and efficiently detect MALT1 enzymatic activitys, and will
Be applied to high flux screening MALT1 micromolecular inhibitors.Pass through 30,000 small molecules of high flux screening
Compound, the present inventor screens step card of going forward side by side, confirms that 1 IC50 is less than 1nM and has good
The micromolecular compound of dose-response curve.Described micromolecular compound is referred to as WX28, its structure
Formula is as follows：
Present invention additionally comprises WX28 isomers, solvate, precursor, or they pharmaceutically can connect
The salt received, as long as they have identical or essentially identical function with WX28.Described " pharmaceutically may be used
The salt of receiving " refers to the reaction generation such as compound and inorganic acid, Organic Acid and Base metal or alkaline-earth metal
Salt.These salt include but is not limited to：(1) with the salt of following inorganic acid formation：Such as hydrochloric acid, sulfuric acid, nitre
Acid, phosphoric acid；(2) with the salt of following organic acid formation, such as acetic acid, oxalic acid, succinic acid, tartaric acid, first
Sulfonic acid, maleic acid or arginine.Other salt include and alkali metal or alkaline-earth metal (such as sodium, potassium, calcium
Or magnesium) formed salt, in the form of ester, carbamate, or other conventional " pro-drugs ".Change
Compound has one or more asymmetric centers.So, these compounds can be used as racemic mixing
It is thing, single enantiomter, single diastereoisomer, non-enantiomer mixture, cis
Or transisomer is present.
Described " precursor of compound " refers to after being taken with appropriate method, and the precursor of the compound exists
It is metabolized or is chemically reacted in patient body and the compound of transition cost invention, or the change containing the present invention
The salt or solution of compound.
Those skilled in the art should be understood that after the structure of the compounds of this invention is known, and can pass through a variety of
Method known to field, using known raw material, to obtain the compound of the present invention, such as chemical synthesis
Or from biological (such as animal or plant) the middle method extracted, these methods are included in the present invention.
The compound of synthesis can be with further further by modes such as column chromatography, high performance liquid chromatographies
Purifying.
New discovery based on the present inventor, the invention provides the compound of the present invention or its isomers, molten
Agent compound, precursor, or their pharmaceutically acceptable salt purposes, for preparing MALT1 inhibitor.
Described MALT1 inhibitor prevention or the big B for the treatment of MALT1 activity dependent enzymes tumour such as diffusivity
Cell lymphoma, particularly activating B cell type (ABC-DLBCL) diffusivity large B cell lymphoid tumor.
As used herein, term " MALT1 dependent tumors " and " MALT1 activity dependent enzymes tumour "
Or " tumour dependent on MALT1 activity " is used interchangeably.
Pharmaceutical composition
Present invention also offers a kind of pharmaceutical composition for being used to suppress MALT1, contain：(a) effective dose
WX28 compounds of the present invention or its isomers, solvate, precursor, or their medicine
Acceptable salt on；Pharmaceutically acceptable carrier or excipient (b).Described pharmaceutical composition can
For preventing or treating MALT1 dependent tumors such as diffusivity large B cell lymphoid tumor, particularly activate
B cell type (ABC-DLBCL) diffusivity large B cell lymphoid tumor.
In the present invention, " pharmaceutically acceptable " composition apply to people and/or animal and without excessively bad
Side reaction (such as toxicity, stimulation and allergy) be have rational benefit/risk than material.
In the present invention, " pharmaceutically acceptable carrier " be for by the present invention compound, its isomery
Body, solvate, precursor, or their pharmaceutically acceptable salt send animal or people to pharmaceutically
Or acceptable solvent, suspending agent or excipient on food.Carrier can be liquid or solid.
In the present invention, described pharmaceutical composition contains according to this hair that part by weight is 0.0001-50%
Bright compound, its isomers, solvate, precursor, or their pharmaceutically acceptable salt.Compared with
Good, described pharmaceutical composition contains according to the compound of the invention that part by weight is 0.001-20%,
Its isomers, solvate, precursor, or their pharmaceutically acceptable salt.The compound of the present invention
As active component effective application dosage can with the pattern of administration and the order of severity of disease to be treated and
Change.
The formulation of pharmaceutical composition of the present invention can be diversified, as long as activity can be made
The formulation that composition effectively reaches mammalian organism is all possible.Such as can be powder-injection, injection
Agent.According to the convenience and demand for the treatment of, those skilled in the art can select the convenient formulation applied.This hair
Bright compound or its pharmaceutical composition can be also stored in the disinfector for being suitable for injecting or instiling.
Screening technique
The present invention establishes the activity that fluorescence radiation method detects MALT1, to more than 30,000 small molecule chemical combination
Thing carries out high flux screening.By screening and checking, obtained the present invention can effectively suppress MALT1
Enzymatic activity micromolecular compound.
Therefore, the present invention also provides a kind of method of screening MALT1 inhibitor, and methods described includes：(1)
MALT1 class Caspase domain fragments are merged with leucine zipper dimer fragment, obtained
LZ-MALT1 recombination fusion proteins；(2) by the recombination fusion protein of candidate substances and step (1) and
MALT1 substrate specificities are contacted；(3) fluorescent value of the AMC fluorophors generated in the system of detection (2),
If adding fluorescent value after candidate substances occurs conspicuousness reduction, then the candidate substances are that MALT1 suppresses
Agent.
In a preferred embodiment of the present invention, it is mutual in order to be more easily observable enzyme-to-substrate when being screened
The change of effect, also can be set control group, described control group can be the institute without the candidate substances
The recombination fusion protein and the Interaction System of MALT1 substrate specificities stated.
In a preferred embodiment of the present invention, when being screened, positive control is also set up, is produced with positive control
Raw fluorescent value is as reference, so that the degree of accuracy of the screening improved.
As the preferred embodiment of the present invention, described method also includes：Traveling one is entered to the potential material of acquisition
The cell experiment and/or animal experiment of step, further to select and determine for suppressing MALT1 and then pressing down
The MALT1 dependent tumors processed such as significantly more material of diffusivity large B cell lymphoid tumor effect.
The suppression MALT1 obtained using screening technique of the present invention potential material may make up a sieve
Select storehouse, in order to people may finally therefrom filter out for suppress MALT1 so that suppress MALT1 according to
Rely the property tumour such as significantly more material of diffusivity large B cell lymphoid tumor effect.
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are only used for
Illustrate the present invention rather than limitation the scope of the present invention.The reality of unreceipted actual conditions in the following example
Proved recipe method, generally writes, Molecular Cloning:A Laboratory guide according to normal condition such as J. Pehanorm Brookers etc., the
Three editions, Science Press, the condition described in 2002, or according to the condition proposed by manufacturer.
Embodiment 1, LZ-MALT1 Protein expression and purifications
Because the MALT1 of total length and its class caspase domains (340-789 amino acid) are in physiology
It is to exist as monomer in solution, digestion activity is relatively low, MALT1 needs to form dimer ability more preferably
Ground plays digestion activity.Study by analysis, the present inventor is by MALT1 class caspase domains
(340-789) fragment is merged with leucine zipper dimer fragment, has been built into LZ-MALT1 external weight
Histone.
Following (the SEQ ID NO of MALT1 (340-789) amino acid sequence:1)：
AKDKVALLIGNMNYREHPKLKAPLVDVYELTNLLRQLDFKVVSLLDLTEY
EMRNAVDEFLLLLDKGVYGLLYYAGHGYENFGNSFMVPVDAPNPYRSEN
CLCVQNILKLMQEKETGLNVFLLDMCRKRNDYDDTIPILDALKVTANIVFG
YATCQGAEAFEIQHSGLANGIFMKFLKDRLLEDKKITVLLDEVAEDMGKC
HLTKGKQALEIRSSLSEKRALTDPIQGTEYSAESLVRNLQWAKAHELPESM
CLKFDCGVQIQLGFAAEFSNVMIIYTSIVYKPPEIIMCDAYVTDFPLDLDIDP
KDANKGTPEETGSYLVSKDLPKHCLYTRLSSLQKLKEHLVFTVCLSYQYSG
LEDTVEDKQEVNVGKPLIAKLDMHRGLGRKTCFQTCLMSNGPYQSSAATS
GGAGHYHSLQDPFHGVYHSHPGNPSNVTPADSCHCSRTPDAFISS
Leucine zipper dimer fragment is made up of the amino acid of GCN4 (251-281), sequence following
3-33 (" HM " restriction enzyme sites sequence in following sequence)：
HMKQLEDKVEELLSKNYHLENEVARLKKLVGER(SEQ ID NO:2)；
Have between GCN4 (251-281) slide fastener fragments and MALT1 (340-789) fragment by
“GSGSGSGS(SEQ ID NO:3) " the stuffer fragment of composition, for separating the two fragments, with
Avoid steric hindrance.Form LZ-MALT1.
The LZ-MALT1 (340-789) of foregoing acquisition amplified production is inserted in Nde1/Not1 restriction enzyme sites
In (being purchased from Novagen) in pET-28a plasmids, the recombinant plasmid containing fusion fragment is obtained.
The recombinant plasmid transformed of foregoing acquisition is expressed into Rosetta cell lines, passed through
Ni-NTA (Qiagen, Valencia, CA) affinity chromatography preliminary purification, then pass through gel filtration chromatography post
Superdex 200HR 10/300 (GE Healthcare, UK) are further purified, and collect destination protein
LZ-MALT1。
Such as Fig. 1 is shown, is started destination protein peak occur in 12-14mL or so position, is used SDS-PAGE
Glue verifies the albumen strictly LZ-MALT1 under this peak shape, and purity is more than 95%.By acquisition
LZ-MALT1 protein storages are in Tris containing 20mM (pH 7.5), 150mM NaCl and 5mM DTT
Buffer solution in.
The high flux screening of embodiment 2, LZ-MALT1 specific small molecule inhibitor
LZ-MALT1 and Ac-LVSR-AMC is included in the screening system that the present inventor sets up, wherein
Ac-LVSR-AMC is MALT1 substrate specificity, and MALT1 can recognize LVSR sites and carry out
Cutting, the AMC groups discharged can send fluorescence, therefore can be characterized by the fluorescent value detected
MALT1 enzymatic activity.To determine the reaction condition of optimal high flux screening, the present inventor is provided with
A series of LZ-MALT1 concentration (25nM, 50nM, 100nM, 200nM etc.) and concentration of substrate (62.5uM,
125uM, 250uM etc.), two-dimensional quadrature experiment is done, was detected every 30 seconds and records fluorescent value, as a result
As shown in Fig. 2 linear relationship is presented with the time in fluorescent value, with the increase of concentration of substrate, reaction signal
Increase, as enzyme concentration increases, reaction signal also accordingly increases, and further demonstrates purifying
LZ-MALT1 has good activity, can be used for follow-up high flux screening.
Ac-LVSR-AMC：Shone by force biosynthesis by Shanghai.
The present inventor assesses screening quality with Z factor, Z factor be a kind of evaluating data degree of variation and
The coefficient of dynamic range is reacted, calculation formula is：1-3*(σp+σn)/(|μp-μn|), wherein σp/nBe sun/
The standard deviation of negative control, μp/nIt is the average value of male/female property control, wherein Z factor was more than for 0.5 generation
Table experiment can efficiently differentiate signal and noise, available for high flux screening (S.Inst and B.Parent, " A
simple statistical parameter for use in evaluation and validation of high
throughput screeining assays,”J.Biomol.Screen.,vol.4,no.2,pp.67–74,
1999)。
Consider the effect and enzyme and substrate consumption of high flux screening, the present inventor have finally chosen 25nM
LZ-MALT1 and 80 μM of Ac-LVSR-AMCc combination, it is right using Z-VRPR-FMK as the positive
According to, to comprise only the BufferA of substrate as negative control, after reaction 90 minutes, Z factor is 0.699,
In the range of optimal 0.5-1.
Based on the studies above, high flux screening reaction system is set up as follows：By the material measured as shown in table 1
It is added to Buffer A (20mM HEPES pH 7.5,10mM KCl, 1.5mM MgCl2, 1mM
EDTA, 1mM DTT, 0.01%Triton X-100) in, 20 μ l/ holes.
Table 1
| LZ-MALT1 | 25nM |
| Ac-LVSR-AMC | 80μM |
| Compound to be tested | 10μM |
Reaction is at 384 orifice plates (Greiner Bio One, Wemmel, Belgium, Catalogue#784076)
It is middle to be reacted, examined with Envision Multilabel Reader (Perkin-Elmer, Waltham, MA)
Reaction fluorescence signal is surveyed, launch wavelength and excitation wavelength are 360nm and 465nm respectively.In order to not omit
The inhibitor combined at a slow speed, LZ-MALT1 and testing compound are first in room temperature preincubate 30 minutes, so
After add substrate A c-LVSR-AMC, add Ac-LVSR-AMC after 0 minute and 90 minutes
When detect respectively and tracer signal.To exclude the spontaneous luminous effect of compound, with two time point signals
Difference (T90-T0) characterizes MALT1 activity.
Finally the formula of inhibiting rate is：[testing compound fluorescence(T90-T0)- negative control fluorescence(T90-T0)]/[is positive
Property control fluorescence(T90-T0)- negative control fluorescence(T90-T0)]*100。
Wherein, it is positive control with known MALT1 inhibitor 50nM Z-VRPR-FMK, containing only
The BufferA for having substrate is negative control.Inhibiting rate using 40% is screened as threshold value.
As a result, 30007 compounds in compound library (being obtained from the bright Kant of medicine) have been screened altogether.
The compliance test result of embodiment 3, compound
Screening the micromolecular compound obtained for embodiment 2, these are changed by dose-response experimental verification
The effect of compound, using half inhibiting rate concentration (IC50) be less than 20 μM and have good dose-effect curve as
Standard.
From these compounds, obtaining 1, inhibitory action is strong, dose-response curve is S-type, IC50
Micromolecular compound less than 1nM is used as MALT1 inhibitor, such as Fig. 3 and table 2.
Table 2
The compound of table 2 can effectively suppress MALT1 activity in vitro, be effective MALT1
Inhibitor, can be applied to clinical treatment ABC-DLBCL targeted drug.
Embodiment 4, candidate compound are to ABC-DLBCL cell lines specifically growth inhibition effect
MALT1 activity plays an important roll for the propagation of ABC-DLBCL cells, and
The positive inhibitor of ABC-DLBCL cells and GCB-DLBCL cells for MALT1
Z-VRPR-FMK sensitiveness is different.
WX28 is the micromolecular inhibitor that IC50 values are minimum, effect is best in enzyme activity Inhibition test in vitro.
The present inventor further verifies its inhibition by cell growth inhibition assay.
In order to examine the present invention screening obtain micromolecular compound WX28 to ABC-DLBCL whether
With optionally inhibitory action, the present inventor using various concentrations gradient (0.01uM, 0.1uM, 1uM,
10uM, 100uM) WX28 act on two kinds of ABC-DLBCL cell lines i.e. HBL-1, TMD8
On a kind of GCB-DLBCL cell lines OCI-LY1 (each cell line is purchased from ATCC), 0h and 72h
After determine cell quantity.
Cell growth inhibition assay result shows that compound WX28 can play inhibitory action, and suppress
The ability of ABC-DLBCL cell line TMD8 cells is ideal, such as Fig. 4.
Therefore, compound WX28 has efficient cytostatic potentiality.
Discuss
ABC-DLBCL is current grade malignancy highest lymthoma, immune to what is clinically commonly used at present
Chemical R-CHOP therapies have strong drug resistance.One of its feature is with growth promotion, anti-apoptotic work
The sustained activations of NF- κ B signal paths, therefore, in theory for, find targeted drug and hinder
NF- κ B signals in ABC-DLBCL are the effective ways for treating ABC-DLBCL.But, due to
NF- κ B are the transcription factors with extensive important biomolecule activity, and itself is not appropriate for as therapy target.
In B cell, Src family kinase phosphorylations CD79A and CD79B are induced after antigen binding BCR
ITAM domains tyrosine, then, EGFR-TK Syk is by being attached to the ITAM of phosphorylation
On be activated so that triggered including bruton's tyrosine kinase (Bruton ' s tyrosine kinase,
BTK), phosphatase C γ (phospholipase C γ) and protein kinase C β (protein kinase C β, PKC- β)
Signal cascade reaction inside.PKC- β make CARM1 occur phosphorylation, promote it recruit BCL10 and
MALT1, forms CBM compounds, so as to activate I kappa b kinases (IKK), finally excites NF- κ B
Signal path.On the other hand, the MALT1 of activation passes through the cutting inactivation of its enzymatic activity A20, CYLD
Deng NF- κ B negative feedback inhibition agent, further promote the activation of NF- κ B signal paths.
The mutation or indexing of common above signal path molecule in ABC-DLBCL tumour cell, for example
CARMA1 mutation, CD79A/B mutation, indexing of BCL10 and MALT1 genes etc., cause NF- κ B
The persistent activation of signal path.
Therefore, CBM complexs play an important role in mediation NF- kB activations.And CBM is compound
Unique MALT1 albumen with enzymatic activity is the ABC-DLBCL of exploitation treatment in recent years targeting in body
The popular molecular target of medicine：First, suppressing MALT1 activity can effectively suppress NF- κ B's
Signal, so that selective depression even kills ABC-DLBCL cells, illustrates to target MALT1 enzyme activity
Treatment validity；Secondly, the mouse that MALT1 is knocked out is except in the activation side of T cell and B cell
Face shows a part of defect, and all phenotype is normal in other respects, points out targeting MALT1 enzyme activity to control
The side effect for treating ABC-DLBCL can be smaller；3rd, MALT1 class caspase domains are in people
It is unique in genoid, suppressing MALT1 will not produce due to suppressing similar albumen of other structures etc.
The extensive side effect caused.
In recent years, find MALT1 targeted inhibition agent turns into study hotspot, but more existing
The problem of compound inhibitor has different, druggability in itself is poor, is difficult to further clinic and opens
Hair.Therefore, the more effective more preferable MALT1 inhibitor of druggability is developed to treatment ABC-DLBCL
It is significant.
The present inventor has carried out high flux by setting up the model of high flux screening to 30007 small molecules
Screening, therefrom obtains the compound WX28 that an IC50 is less than 1nM.The present invention is exploitation MALT1
Targeted drug provide good basis treating ABC-DLBCL and ensure.
All documents referred in the present invention are all incorporated as reference in this application, just as each text
Offer and be individually recited as with reference to such.In addition, it is to be understood that reading the above-mentioned instruction content of the present invention
Afterwards, those skilled in the art can make various changes or modifications to the present invention, and these equivalent form of values are same
Fall within the application appended claims limited range.
Claims (9)
1. the use of compound or its pharmaceutically acceptable salt or precursor in MALT1 inhibitor is prepared
On the way；Wherein, the structural formula of described compound is：
2. purposes as claimed in claim 1, it is characterised in that described MALT1 inhibitor prevention
Or treatment MALT1 dependent tumors.
3. purposes as claimed in claim 2, it is characterised in that described MALT1 dependent tumors
Including：Diffusivity large B cell lymphoid tumor.
4. purposes as claimed in claim 1, it is characterised in that described diffusivity large B cell lymph
Knurl is activating B cell type diffusivity large B cell lymphoid tumor.
5. the purposes as described in claim 1-4 is any, it is characterised in that described compound passes through suppression
MALT1 processed, and then suppress the CBM of CARMA1 or its family protein, BCL10 and MALT1 compositions
Compound, so as to play prevention or therapeutic action.
6. purposes as claimed in claim 5, it is characterised in that described CARMA1 family's egg
It is white to include but is not limited to：CARMA2, CARMA3, CARD9.
7. a kind of method for preparing MALT1 inhibitor, it is characterised in that methods described includes：It will change
Compound is mixed with pharmaceutically acceptable carrier, obtains MALT1 inhibitor；The knot of described compound
Structure formula is：
8. method as claimed in claim 7, it is characterised in that described MALT1 inhibitor prevention
Or treatment MALT1 dependent tumors.
9. method as claimed in claim 8, it is characterised in that described MALT1 dependent tumors
Including but not limited to：Activating B cell type diffusivity large B cell lymphoid tumor.
Priority Applications (1)
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| CN110950807A (en) * | 2018-09-26 | 2020-04-03 | 中国科学院上海药物研究所 | Biaryl compound, preparation method thereof, pharmaceutical composition and application thereof |
| CN110960525A (en) * | 2019-11-26 | 2020-04-07 | 济南大学 | Identification and evaluation of novel EED-EZH2 interaction inhibitors |
| CN115677617A (en) * | 2022-11-04 | 2023-02-03 | 济南大学 | Compound targeting c-Src kinase SH3 structural domain and application thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110950807A (en) * | 2018-09-26 | 2020-04-03 | 中国科学院上海药物研究所 | Biaryl compound, preparation method thereof, pharmaceutical composition and application thereof |
| CN110950807B (en) * | 2018-09-26 | 2023-03-03 | 中国科学院上海药物研究所 | Biaryl compound, preparation method thereof, pharmaceutical composition and application thereof |
| CN110960525A (en) * | 2019-11-26 | 2020-04-07 | 济南大学 | Identification and evaluation of novel EED-EZH2 interaction inhibitors |
| CN115677617A (en) * | 2022-11-04 | 2023-02-03 | 济南大学 | Compound targeting c-Src kinase SH3 structural domain and application thereof |
| CN115677617B (en) * | 2022-11-04 | 2023-12-26 | 济南大学 | Compound targeting c-Src kinase SH3 structural domain and application thereof |
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