CN106692155A - Application of small-molecular inhibitor SC13 targeting to FEN1 and derivative of small-molecular inhibitor SC13 in preparing tumor treatment medicine - Google Patents
Application of small-molecular inhibitor SC13 targeting to FEN1 and derivative of small-molecular inhibitor SC13 in preparing tumor treatment medicine Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses application of a small-molecular inhibitor SC13 targeting to FEN1 (Fragment Endonuclease) and a derivative of the small-molecular inhibitor SC13 in preparing a tumor treatment medicine. The small-molecular inhibitor SC13 targets to FEN1 protein, has very good anti-tumor activity and good physicochemical properties, and has an effective anti-cancer effect in high-expression FEN1 breast cancer. A novel idea and a mechanism are provided for an FEN1 small-molecular inhibitor, and the small-molecular inhibitor SC13 has the potential of being developed into clinical anti-cancer medicines.
Description
Technical field
The invention belongs to biomedicine field, it is related to a kind of new small molecule for being directed to DNA fragmentation endonuclease 1 to press down
Preparation.FEN1 activity can specifically be suppressed, be that treatment of cancer is carried so as to disturb DNA replication dna and reparation in vitro and in cell
For new scheme and support.
Background technology
DNA fragmentation endonuclease 1 (FEN1) by participating in DNA replication dna and reparation, maintain genome stability and
Key effect is played in integrality.FEN1 is a kind of metalloproteinase nucleic acid enzyme, with structural specificity, by a Core domain and one
Bar tail chain is constituted.It is different from other restriction enzymes, and the substrate for being recognized is unrelated with sequence, only recognizes specific DNA
Structure.In addition to endonuclease (FEN) activity, also exonuclease (EXO) activity and breach endonuclease (GEN) are living
Property, FEN1 is because these three activity of itself so that it plays the part of role of crucial importance in many DNA metabolic pathways, such as
The degraded of DNA fragmentation, the maintenance of Telomere Stability, primer goes in long segment base excision repair (LP-BER) and lagging strand
Except etc..FEN1 can interact from different protein, there is abnormal expression, this exception in tumour cell
Expression is probably a kind of potential tumor-marker.
The suppression of FEN1 can cause that DNA replication dna blocks and the DNA intermediate do not repaired can be accumulated in cell, so as to lead
Cause DNA double chain fracture and Apoptosis.Therefore, targeting FEN1 can be as the effective strategy for the treatment of of cancer.Research shows
FEN1 overexpression in breast cancer, and necessary to being the fast breeding of cancer cell.In addition the water of FEN1 is regulated and controled in cell
It is flat to influence response of the cancer cell to chemotherapeutics.
So far, breast cancer is still the most common cancer of women, and its incidence of disease persistently rises, thus research and development it is new and
The medicine of effective treatment breast cancer seems extremely urgent.Research shows that FEN1 is overexpression in breast cancer cell, and
MCF7 breast cancer cell lines are used in this patent as research model, it was demonstrated that propagation and drug resistance of the FEN1 for breast cancer cell
It is essential.
Based on background above, one new FEN1 inhibitor --- SC13 of invention.This compound is special
Property ground suppress FEN1 activity, so as to disturb DNA replication dna and reparation in vitro and in cell.In cell, SC13 suppresses cancer cell
Breed and induced chromosome is unstable and cytotoxicity, make cancer cell more sensitive to DNA damage reagent.Importantly,
In mouse model, SC13 causes tumours of chemotherapeutic agents enhanced sensitivity, reduces the dosage and toxic and side effect of chemotherapeutics, hinders
The process of tumor development.These discoveries can set up a new example to treat breast cancer and other cancers.
The content of the invention
The answering in treatment of cancer it is an object of the invention to provide a kind of micromolecular inhibitor for targeting FEN1 albumen
With for current treatment of cancer provides effective measures.
The technical solution adopted in the present invention is：
The specific small molecule inhibitor SC13 and its derivative compound for targeting FEN1 albumen are preparing treatment tumour medicine
Application in thing.
Further, SC13 can form hydrogen bond with S36, T134, N138 and D233 of FEN1 albumen, suppress the work of FEN1 albumen
Property.
Further, the micromolecular inhibitor SC13 and its derivative of FEN1 are targeted, wherein SC13 has structure shown in formula I：
The basic structure of its derivative is as shown in formula II：
Wherein R1 can form the compound of acid amides, such as：
R2 aromatic series and aliphatic compound, such as：
It is the aliphatic of 1-8 Deng carbon number, can is straight chain, or
Side chain；Or such as：
Deng aromatic compound.
The micromolecular inhibitor that one class targets FEN1 albumen is preparing the breast cancer and other cancers for the treatment of FEN1 expression high
Application in disease drug.
One class target the micromolecular inhibitor of FEN1 albumen and other chemotherapeutics for example cis-platinum, taxol, 5FU,
The Drug combinations such as BYK204165 are treating the breast cancer of FEN1 expression high, stomach cancer, colorectal cancer, lung cancer and other FEN1
Application in the cancer of height expression.
Prominent effect of the invention is：Micromolecular inhibitor SC13 of the invention targets FEN1 albumen, with good
Antitumor activity and good physicochemical property, with effective anticancer effect especially in the breast cancer of height expression FEN1 in the present invention
Really.The present invention provides new thinking and mechanism for FEN1 micromolecular inhibitors, there is the potentiality for developing into clinical anti-cancer medicine.
Specific embodiment of the invention will be below further elaborated by embodiment and diagram.
Brief description of the drawings
Fig. 1 is SC13 screenings and structural representation.
Fig. 2 is FEN1 and SC13 interaction schematic diagrames.
Fig. 3 displays SC13 does not suppress the binding activity of FEN1 and DNA substrates.
Fig. 4 displays SC13 specifically suppresses the activity of FEN1 albumen.
Fig. 5 shows SC13 by targeting FEN1 albumen and inducing cytotoxic.
Fig. 6 displays SC13 makes cancer cell more sensitive with being used in combination for chemotherapeutics.
Heteroplastic transplantation experiment checking Drug combination causes that tumour is more sensitive in Fig. 7 display bodies.
Specific embodiment
The present invention is a kind of micromolecular inhibitor for being directed to FEN1 albumen, the material used in embodiment described below
Material, reagent etc., unless otherwise specified, commercially obtain.
The screening of embodiment 1, FEN1 specific small molecule inhibitor
Background introduction according to more than, the present invention is by FEN1 as a target spot for treating cancer, then target FEN1
Micromolecular inhibitor can be as an effective antitumour medicine.
(1) screening of tumour medicine：Tumey et al. early-stage Studies show that N- dihydroxy urea derivative has suppression to FEN1 albumen
Make and use.The half amount inhibiting rate IC50 of compound #20 (Figure 1A) is 3nM, is that the optimal FEN1 of vitro detection binding ability suppresses
Agent.However, compound #20 is used alone, suppress the limited in one's ability of growth of cancer cells.We are designed based on #20 compounds
Two kinds of totally 6 new micromolecular compounds (Figure 1B).Two groups of pharmacophoric groups of micromolecular compound are respectively pyrroles-[3,2-
D] pyrimidine (SC11, SC12, and SC13) and thiophene-[3,2-d] pyrimidine (SC21, SC22, and SC23).To detect the structure effect of medicine
Relation, improves the transparency of compound on intracellular, and hydrophilic hydroxy group group is substituted by hydrophobic phenyl, benzyl, propyl group.
In several compounds, SC13 shows stronger FEN1 inhibitor activities (Fig. 1 C), and with more preferable cell permeability.
(2) determination of SC13 and FEN1 interaction sites：5 optimal drug binding sites are have found by docking research method,
An optimal drug binding site is wherein determined ----site 1 (Fig. 2A), the combination of SC13 and FEN1, be by with S36,
T134, N138 and D233 form hydrogen bond (Fig. 2 B).It is afterwards S36A, T134A, N138A, and D233A by mutating experiment, shows
These residues take part in the correlated process (Fig. 2 C) that SC13 suppresses FEN1 activity.
The mechanism that embodiment 2, SC13 and FEN1 interact
(1) SC13 does not influence the activity of FEN1 and DNA Binding Capacities：We have used DNA Binding experiments to enter in the present embodiment
Row checking.In short, being first coated with 96 orifice plates with Streptavidin, 4 DEG C overnight, 3%BSA room temperatures closing 2h, uses respectively afterwards
Unlabelled and biotin labeling DNA substrates are reacted, and add the FEN1 albumen and inhibitor SC13 of various concentrations, then
Corresponding primary antibody and secondary antibody, last TMB color development at room temperature, 2M sulfuric acid terminating reactions, 450nm is added to absorb reading under light.It is real
Result is tested to show：Although SC13 is combined with the activated centre of FEN1, the combination (Fig. 3) of FEN1 and DNA substrates is had no effect on.
(2) SC13 specifically suppresses the activity of FEN1 albumen：In order to further confirm that SC13 be it is selectively targeted in
FEN1 protein actives, whether the present invention also influences enzyme such as APE1, Pol β, the and DNA in other BER reparation approach to SC13
The enzymatic activity of ligase I is studied, and as a result shows that SC13 does not influence on the enzyme activity of these enzymes, and this shows SC13 specificity
Ground suppresses the activity (Fig. 4) of FEN1 albumen.
Embodiment 3, SC13 by target FEN1 albumen and inducing cytotoxic
(1) MCF7 cells are processed respectively with the SC13 of various concentrations and FEN1 strikes the MCF7 cells of drop, the increasing of observation of cell
Grow situation.Result display SC13 induces the toxicity of MCF7 cells, but cannot then cause cell toxicant in FEN1 strikes the cell of drop
Property.This explanation SC13 is by targeting FEN1 albumen and inducing cytotoxic (Fig. 5 A, B).
(2) BYK204165 is used in combination with SC13, as a result causes cell greater area of compared to exclusive use SC13
Dead (Fig. 5 C).
(3) breast cancer cell line that HR approach is lacked is processed with SC13 --- HCC1937 (BRAC-/-), as a result show this
Individual cell line is more sensitive to SC13 than MCF7 cell.These results show in the case where HR is lacked, because the activity of FEN1 is pressed down
System, the DNA double chain fracture of generation cannot be repaired, and then accelerate the dead process (Fig. 5 D) of cell.
Embodiment 4, SC13 enhances sensitiveness of the cancer cell to chemotherapeutics
The example of Drug combination in embodiment 3, for the present embodiment is provided according to and is supported.Mainly said in the present embodiment
Bright SC13 can strengthen sensitiveness of the cancer cell to various chemotherapeutics, for clinical cancer therapy provides new medication combined make
Example.
(1) SC13 makes cancer cell more sensitive with being used in combination for chemotherapeutics：Various chemotherapeutics are combined with SC13
It is more sensitive when Fig. 6 shows that cancer cell is individually processed relative to medicine during using treatment cell.But the cell knocked out in FEN1
In, cancer cell declines for the sensitiveness of Drug combination.
(2) Drug combination of heteroplastic transplantation experiment checking in vivo causes that tumour is more sensitive：Mainly used in the present embodiment
Be 6 weeks big homozygous female nude mices.MCF7 cells are made suspension, and living cell rate is more than 95%, by the cell suspension of equivalent
BD matrigels with equivalent are mixed, and hypodermic injection enters the back right side of nude mice.Treat that tumour is formed, continuous 5 days by nude mice abdominal cavity
Treatment is administered daily, every group of gross tumor volume is periodically measured.Result shows that Drug combination makes the tumour of heterograft
Model is more sensitive to medicine (Fig. 7).
Claims (6)
1. applications of a kind of micromolecular inhibitor SC13 and its derivative for targeting FEN1 in the medicine for preparing treatment tumour；
SC13 has structure shown in formula I：
The basic structure of SC13 derivatives is as shown in formula II：
Wherein R1 can be the compound to form acid amides, and R2 is aromatic series and aliphatic compound.
2. application according to claim 1, it is held to levy and is, R1 structures are：
3. application according to claim 1, it is held to levy and is, R2 is the aliphatic that carbon number is 1-8.
4. application according to claim 1, it is characterised in that the medicine for the treatment of tumour is the mammary gland for treating FEN1 expression high
Cancer and other cancer drugs.
5. the micromolecular inhibitor SC13 and its derivative and other chemotherapy drugs in combination for targeting FEN1 albumen are used and prepared
Application in the cancer drug of breast cancer, stomach cancer, colorectal cancer, lung cancer and other FEN1 expression high for the treatment of FEN1 expression high.
6. application according to claim 5, it is characterised in that described other chemotherapeutics be cis-platinum, taxol, 5FU or
BYK204165。
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110279704A (en) * | 2019-07-30 | 2019-09-27 | 南京师范大学 | Adriamycin drug and its application |
| CN112121183A (en) * | 2020-09-09 | 2020-12-25 | 南京师范大学 | Fluorescent multi-mode molecular imaging and drug loading breast cancer diagnosis and treatment integrated nanoprobe and preparation method and application thereof |
-
2017
- 2017-01-13 CN CN201710023851.1A patent/CN106692155A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| L. HE ET AL.: "Targeting DNA Flap Endonuclease 1 to Impede Breast Cancer Progression", 《EBIOMEDICINE》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110279704A (en) * | 2019-07-30 | 2019-09-27 | 南京师范大学 | Adriamycin drug and its application |
| CN110279704B (en) * | 2019-07-30 | 2022-08-26 | 南京师范大学 | Adriamycin combined medicine and application thereof |
| CN112121183A (en) * | 2020-09-09 | 2020-12-25 | 南京师范大学 | Fluorescent multi-mode molecular imaging and drug loading breast cancer diagnosis and treatment integrated nanoprobe and preparation method and application thereof |
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