CN102805860A - Inhibitor for acetylation of pyruvate kinase 2 (PKM2) and use thereof - Google Patents
Inhibitor for acetylation of pyruvate kinase 2 (PKM2) and use thereof Download PDFInfo
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Abstract
The invention relates to an inhibitor for acetylation of pyruvate kinase 2 (PKM2) and a use of the inhibitor, belonging to the field of molecular biology and medicine. The inhibitor for acetylation of pyruvate kinase 2 comprises a PKM2K305 acetylation inhibitor which can effectively inhibit acetylation of K305. The invention further provides an antibody and a method for detecting acetylation of PKM2K305 correspondingly. The detection method can detect the acetylation level of PKM2K305 in a tumor sample, and is simple and practicable, fast and efficient, and low in cost. The method is used to detect the acetylation level of PKM2K305 and the acetylation of PKM2K305 is inhibited, and therefore, a simple and convenient novel path for diagnosis and treatment of tumor metabolism is provided.
Description
Technical field
The invention belongs to molecular biology and medical domain, relate to a kind of pyruvate kinase 2 (PKM2) acetylation inhibitor and uses thereof, also relate to and detect acetylizad antibody of PKM2K305 and detection method.
Background technology
Tumor belongs to metabolic disease and stems from Otto Warburg and propose tumor cell metabolism notion the thirties in eighties of last century; Be that cellular metabolism adjusting (like embryo or tumor) is different from the normal mature cell in the mushroom tissue; Through glycolysis or Warburg effect; Cancerous cell absorbs glucose and produce power and growth (Warburg, 1956) fast than other cells with higher efficient.Research shows; Normal cell only carries out glycolysis under anoxybiotic situation; Even and tumor cell also preferentially carries out glycolysis under not anoxybiotic situation; Consume more glucose and produce more lactic acid, famous Warburg effect that Here it is, therefore Mr. Warburg also obtained Nobel Prize in medicine.Medical circle has been carried out correlational study widely subsequently; More and more evidences shows that cellular metabolism plays important effect in the generation of tumor and development; But the molecular mechanism about it is not clear, and many aspects also are worth deeply inquiring into (Mazurek et al., 2005); More noticeablely be; FDG PET image all shows as increasing and metabolic change of glucose absorption in different types of former and the tumor that shifts; Add the breakthrough of cell signal path research and the innovation of laboratory facilities; Especially the extensive application of protein science research means, the research of tumor metabolic regulation becomes the focus of international research again.
Discover that many metabolic enzymes receive acetylizad regulation and control; Follow-up functional study also shows, the acetylation regulation and control of metabolic enzyme in tumor development, possibly play an important role (Choudhary et al., 2009; Zhao et al., 2010).Research is also found; Pyruvate kinase is one of key enzyme in the glycolytic cycle; Only express embryo type pyruvate kinase (PKM2) in embryonal tissue, be expressed as the pyruvate kinase (PKM1) of model year after growing up, but only express PKM2 again at tumor tissues; Rather than PKM1 (Mazurek et al., 2005).Current research shows that PKM2 is that a kind of phosphorylated tyrosine is conjugated protein, and tumor cell proliferation must combine to regulate and control PKM2 activity (Christofk et al., 2008a through phosphorylated tyrosine; Christofk et al., 2008b); In addition, the ratio (David et al., 2009) of the two kinds of spliceosome PKM1 of isomery RNP (HnRNP) the scalable PKM of Myc regulation and control and PKM2.Above-mentioned research shows, the important function of PKM2 in the tumor cell metabolism.In all tumors, all express PKM2 is the focus and the difficult point of puzzled biologist always, and particularly post translational modification and the protein stability thereof about PKM2 do not appear in the newspapers in the world.
The inventor's early-stage Study finds that PKM2 receives acetylizad regulation and control in the prostate cancer tissue sample; The functional study discovery acetylation of carrying out subsequently possibly regulated the active and degraded of metabolic enzyme; Not only in glycolysis, be in the upper reaches that acetone acid produces based on PKM2; And PKM2 exists and is not present in all cancer cell in the normal cell of great majority; Development to tumor cell is again vital simultaneously; Therefore, researcher thinks that PKM2 is the target of potential promising treatment of cancer.
Summary of the invention
The purpose of this invention is to provide a kind of pyruvate kinase 2 acetylation inhibitor.
Further purpose of the present invention provides the purposes of said pyruvate kinase 2 acetylation inhibitor.
Among the present invention, described pyruvate kinase 2 acetylation inhibitor for suppressing the acetylizad inhibitor of PKM2 K305, is characterized in that it contains PKM2K305 acetylation and acetylase and deacetylase described inhibitor.
PKM2K305 of the present invention is arranged in the exon 8 (Homo sapiens 270 KIENHEGVRRFDEILEASDGIMVARGDLGIEIPAEKVFLAQKMM 313) of PKM2, has the sequence like SEQ ID No.1;
Among the present invention, described deacetylase comprises Sirt1, Sirt2, HDAC5, HDAC6, HDAC7,
Described deacetylase causes the deacetylation (as shown in Figure 2) of PKM2K305;
Among the present invention, described acetylase is selected from the sub-PCAF of nuclear receptor coactivity factor 1, and nuclear receptor is assisted activator P300, and histone acetyl based transferase complex GCN5 or carbohydrate-binding protein (=carbohydrate-binding protein, CBP)
Described acetylase causes the acetylation (as shown in Figure 1) of PKM2K305;
Among the present invention, suppress the acetylation (as shown in Figure 3) that acetylase reduces PKM2K305.
Among the present invention, detected the PKM2K305 acetylation in the tumor tissues and expressed, testing result shows that the K305 acetylation in the tumor tissues is apparently higher than cancer beside organism.In one embodiment of the invention, the acetylation level of the acetylation site-specific K305 of carcinoma of prostate and cancer beside organism shows, the acetylation level of PKM2K305 in prostate cancer tissue apparently higher than cancer beside organism; In conjunction with result of study for many years, cause the accumulation of metabolic intermediate through the autophagy and the enzyme work that suppresses PKM2 of molecular chaperones mediation, thereby promote growth of tumor; Wherein, The association study result shows; There is significant difference (p＜0.05) in the acetylation level of PKM2 K305 in 15 routine prostate cancer tissues and cancer beside organism; PKM2K305 acetylation level in tumor tissues is apparently higher than cancer beside organism (as shown in Figure 5), and the acetylation level in said site raises and promotes growth of tumour cell (as shown in table 1).
The ratio data of table 1 K305 acetylation/PKM2.
Result of the test of the present invention has shown that described PKM2 can be tumor treatment new target is provided, and the tumor of treatment comprises carcinoma of prostate; Simultaneously, can expand tumor is taken place and the understanding of Warburg effect.
The invention provides a kind of pyruvate kinase 2 acetylation inhibitor, the acetylizad inhibitor of especially a kind of PKM2K305, this inhibitor can effectively suppress the acetylation of K305;
The present invention further provides a kind of pharmaceutical composition that is used for treatment of cancer, especially to the acetylizad target drug that reduces PKM2K305; Described pharmaceutical composition contains PKM2 acetylase inhibitor and deacetylase or acetylase and pharmaceutically acceptable carrier or excipient safely and effectively; Wherein, described carrier includes, but are not limited to: saline, buffer, glucose, water, glycerol, ethanol and combination thereof;
Described pharmaceutical composition should be complementary with administering mode.
Among the present invention, described pharmaceutical composition can be made into the injection form, as adopting conventional method with normal saline or contain glucose and the aqueous solution of other adjuvant prepares; Described pharmaceutical composition also can adopt conventional method to process tablet and capsule etc.;
Described pharmaceutical composition is made under aseptic condition like injection, solution, tablet and capsule; Wherein, the dosage of active component is the treatment effective dose, like 0.1 microgram/kg body weight-Yue 10 mg/kg body weight every day; In addition, the polypeptide described in the present invention also can use with the other treatment agent.
When using described pharmaceutical composition; Be that the PKM2 acetylase of safe and effective amount and deacetylase or its antagonist, agonist are applied to mammal; Wherein safe and effective dosage is usually at least about 0.1 microgram/kg body weight; And in most of the cases be no more than about 10 mg/kg body weight, preferably safe and effective dosage is about 0.1 microgram/kg body weight-Yue 100 mg/kg body weight; Concrete dosage is factor such as considered route of administration, patient health situation also, and skilled practitioners is not exceeding under the situation of its skill and can prepare voluntarily.
Another object of the present invention provides and detects acetylizad antibody of PKM2 K305 and the acetylizad detection method of PKM2 K305; The acetylizad antibody of described detection PKM2 K305; Be to detect the acetylation antibody that contains acetylation site-specific K305; The polypeptide of preparation K305 acetylation antibody is: acetyl-PKM2 (K305), (polypeptide: IEIPAEKVFLAQ), have the sequence like SEQ ID No.2.Also comprise the acetylation antibody (shown in Figure 6) that detects the site-specific antibody of acetylation-anti-K305 in the detection method.
Among the present invention, the acetylizad detection method of described PKM2 K305 for the acetylation level that detects said site, whether be in growth/recurrence phase with the tumor of the said individuality of auxiliary judgment, may further comprise the steps:
(1) the acetylation antibody of preparation acetylation site-specific K305;
(2) protein of extracting tissue sample/or preparation tumor tissues paraffin section;
(3) detect tumor tissues K305 acetylation level.
In the detection method of the present invention, the polypeptide of preparation K305 acetylation antibody is: acetyl-PKM2 (K305), (polypeptide: IEIPAEKVFLAQ), have the sequence like SEQ ID No.2;
In the said detection method, the AC that detects tumor tissues K305 acetylation level is 1: 500;
In the said detection method, technology such as the protein extraction that relates to, tissue slice, antibody making and SABC all can adopt the routine operation method of this area; Those skilled in the art can carry out protein extraction, tissue slice, antibody making and SABC by described routine operation method.
Detection method of the present invention can be used for the tumor of individuality is detected, and especially carcinoma of prostate of individuality etc. is detected.Using the individual tumor of described PKM2K305 acetylation auxiliary monitoring whether to be in growth/recurrence during the phase, also can use the medicament that reduces its acetylizad other treatment tumor simultaneously.The acetylizad method of a kind of detection tumor PKM2K305 is used to detect tumor growth or recurrence, and the PKM2K305 acetylation level in tumor tissues is apparently higher than cancer beside organism, and is as shown in Figure 5.
The invention provides a kind of pyruvate kinase 2 acetylation inhibitor, relate in particular to the acetylizad inhibitor of a kind of PKM2K305, this inhibitor can effectively suppress the acetylation of K305.The present invention also provides corresponding detecting method, and described detection method can detect the acetylizad level of PKM2K305 in the tumor sample, this detection method is simple, rapidly and efficiently, with low cost; Utilize this method to detect PKM2K305 acetylation level, and suppress, can and treat for tumor metabolism diagnosis simple and direct new way is provided to it.
Description of drawings
Fig. 1 shows that PCAF causes the acetylation of PKM2K305.
Fig. 2 shows that Sirt1 causes the deacetylation of PKM2K305.
Fig. 3 shows that PCAF knocks out the acetylation that causes PKM2K305 and reduces.
Fig. 4 shows that glucose increases the acetylation of PKM2K305.
Fig. 5 shows that K305 acetylation level in the carcinoma of prostate is apparently higher than cancer beside organism.
Fig. 6 is the evaluation figure of K305 acetylation antibody.
The specific embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in the restriction scope of the present invention.The experimental technique of unreceipted actual conditions in the following example, usually according to people such as normal condition such as Sambrook, molecular cloning; Condition described in the laboratory manual (New York:Cold Spring Harbor Laboratory Press, 1989), or the condition of advising according to manufacturer.
SABC detects
One, experiment material
The prostata tissue paraffin section is from core Ji hospital Urology Surgery; PKM2K305 acetylation antibody is provided for oneself; PSA, PKM2 buy from company respectively.
Two, pattern detection:
Experiment detects 15 routine carcinoma of prostate and cancer beside organisms thereof altogether, and every example is collected 5 routine paraffin sections, carries out HE dyeing respectively; PKM2; The acetylizad immuning tissue of PSA and PKM2K305 analyzes, and selects the different visuals field and with software painted intensity is analyzed, the T that matches at last check.
Three, testing result:
The ratio data of table 1 K305 acetylation/PKM2.
As shown in table 1, testing result shows that the PKM2K305 acetylation level in the tumor tissues is apparently higher than the other normal structure of cancer.
Experimental result shows that the PKM2K305 acetylation level in the tumor tissues is apparently higher than the other normal structure of cancer, and described PKM2 can be tumor treatment new target is provided.The present invention can further prepare pyruvate kinase 2 acetylation inhibitor in view of the above, the acetylizad inhibitor of especially a kind of PKM2K305, and further preparation is used for the pharmaceutical composition of treatment of cancer.Pyruvate kinase 2 acetylation inhibitor of the present invention, the acetylizad inhibitor of especially a kind of PKM2K305 can effectively suppress the acetylation of K305.The present invention also provides corresponding detecting method, and described detection method can detect the acetylizad level of PKM2K305 in the tumor sample, and simple, rapidly and efficiently, with low cost; Utilize this method to detect PKM2K305 acetylation level, and suppress to it, diagnosing and treat for the tumor metabolism provides simple and direct new way.
Claims (10)
1. pyruvate kinase 2 acetylation inhibitor is characterized in that, contain PKM2K305 acetylation and acetylase thereof and deacetylase.
2. by the described inhibitor of claim 1, it is characterized in that described PKM2K305 is arranged in the exon 8 of PKM2, has the sequence like SEQ ID No.1.
3. by the described inhibitor of claim 1, it is characterized in that described deacetylase is selected from Sirt1, Sirt2, HDAC5, HDAC6 or HDAC7.
4. by the described inhibitor of claim 1, it is characterized in that described acetylase is selected from PCAF, P300, GCN5 or CBP.
5.PKM2K305 acetylizad antibody is characterized in that, described antibody is the acetylation antibody that contains acetylation site-specific K305, and the polypeptide for preparing this K305 acetylation antibody is: acetyl-PKM2 (K305) has the sequence like SEQ ID No.2.
6. one kind is detected the acetylizad method of PKM2 K305, it is characterized in that, detects the acetylation level in said site, may further comprise the steps:
(1) the acetylation antibody of preparation acetylation site-specific K305;
(2) protein of extracting tissue sample/or preparation tumor tissues paraffin section;
(3) detect tumor tissues K305 acetylation level.
7. by the described method of claim 6, it is characterized in that the polypeptide of the acetylation antibody of the acetylation site-specific K305 of described preparation is acetyl-PKM2 (K305), has the sequence like SEQ ID No.2.
8. by the described method of claim 6, it is characterized in that described tumor tissues K305 acetylation level is that AC is 1: 500.
9. the pyruvate kinase 2 acetylation inhibitor of claim 1 are treated the purposes in the cancer drug in preparation.
10. by the described purposes of claim 9, it is characterized in that described cancer is a carcinoma of prostate.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2014139144A1 (en) * | 2013-03-15 | 2014-09-18 | Agios Pharmaceuticals, Inc. | Therapeutic compounds and compositions |
| CN108653736A (en) * | 2018-04-28 | 2018-10-16 | 中国人民解放军第二军医大学 | Application of the M2 types pyruvate kinase as drug target in the drug for preparing prevention psoriasis |
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| CN102151335A (en) * | 2010-02-12 | 2011-08-17 | 中国科学院上海生命科学研究院 | Regulation of metabolism by protein lysine acetylation modification |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102151335A (en) * | 2010-02-12 | 2011-08-17 | 中国科学院上海生命科学研究院 | Regulation of metabolism by protein lysine acetylation modification |
Non-Patent Citations (2)
| Title |
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| KUN-LIANG GUAN ET AL.: "Generation of acetyllysine antibodies and affinity enrichment of acetylated peptides", 《NATURE PROTOCOLS》 * |
| SHIMIN ZHAO ET AL.: "Regulation of Cellular Metabolism by Protein Lysine Acetylation", 《SCIENCE》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014139144A1 (en) * | 2013-03-15 | 2014-09-18 | Agios Pharmaceuticals, Inc. | Therapeutic compounds and compositions |
| US9108921B2 (en) | 2013-03-15 | 2015-08-18 | Agios Pharmaceuticals, Inc | Therapeutic compounds and compositions |
| US9365545B2 (en) | 2013-03-15 | 2016-06-14 | Agios Pharmaceuticals, Inc | Therapeutic compounds and compositions |
| CN108653736A (en) * | 2018-04-28 | 2018-10-16 | 中国人民解放军第二军医大学 | Application of the M2 types pyruvate kinase as drug target in the drug for preparing prevention psoriasis |
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Application publication date: 20121205 |