WO2018192318A1 - 干扰saicar合成酶活性化合物的应用 - Google Patents
干扰saicar合成酶活性化合物的应用 Download PDFInfo
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- WO2018192318A1 WO2018192318A1 PCT/CN2018/078597 CN2018078597W WO2018192318A1 WO 2018192318 A1 WO2018192318 A1 WO 2018192318A1 CN 2018078597 W CN2018078597 W CN 2018078597W WO 2018192318 A1 WO2018192318 A1 WO 2018192318A1
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- Prior art keywords
- cancer
- acid
- tumor
- pharmaceutically acceptable
- compound
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- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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Definitions
- the present invention relates to the use of compounds that interfere with SAICAR synthetase activity.
- PKM2 Pyruvate kinase isoform M2
- PKM2 Pyruvate kinase isoform M2
- various pharmacological agents against PKM2 enzyme activity affect cell growth and proliferation [5,6], which also suggests that the way to further alter tumor metabolism becomes a new approach to tumor therapy by targeting the enzyme activity of PKM2 [ 7].
- Anthraquinone anabolism is a ubiquitous and important biological metabolism in organisms. Its products AMP and GMP not only provide raw materials for the biosynthesis of DNA and RNA in vivo, but also many key coenzymes in the body (NAD, NADP, FAD and CoA). ), signaling molecules (such as cAMP) and the important energy molecule ATP provide the purine bases necessary for its synthesis. It can be seen that hydrazine anabolism is at the core of the entire metabolic network. Indole synthesis includes two synthetic pathways, de novo purine synthesis and salvage pathway.
- ADSL enzyme adenyl succinate lyase
- SAICAR ribose-50-phosphate
- PAICS is highly expressed in acute lymphocytic leukemia, lung cancer, glioma, prostate cancer, and colorectal cancer, and can be used as a prognostic marker for stage III colorectal cancer [11-13].
- SAICAR high accumulation of SAICAR under glucose-limited conditions alters energy levels, sugar uptake, and lactate production in tumor cells, and these phenomena do not occur in adult epidermal cells and lung fibroblasts [14, 15].
- SAICAR can induce the enzymatic activity of PKM2 and promote the survival of tumor cells [14], and the binding of SAICAR-PKM2 can induce the phosphorylation of Erk1/2, and the high concentration of SAICAR can also induce the up-regulation of oncogene myc [15].
- SAICAR which is abnormally accumulated in the de novo anabolic pathway of adenine, promotes proliferation and survival of tumor cells.
- PAICS phosphoribosylaminoimidazole succinocarboxamide synthetase /phosphoribosylaminoimidazole carboxylase
- SAICAR The function of the enzyme (4-(N-succinylcarboxamide)-5-aminoimidazole ribonucleotide synthetase, SAICARs) and 5-aminoimidazole ribonucleotide carboxylase (AIRc) catalyzes the sixth and seventh steps of de novo anabolism.
- a key reaction process is as follows
- Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiiforme. J Exp Med, 2011.208(2): p.313-26.
- DrugBankID is DB00863, DB05800, DB00585, DB00303, DB00710, DB00451, DB00143, DB01102, DB01255, DB01040, DB00983, DB04983, DB00923, DB05630 based on the existing protein structure data and small molecule structure data.
- the tumor is a tumor having a Warburg effect, a high expression of the oncogene myc, a high expression of PAICS, a correlation with Erk1/2, and a high expression of the PKM2 gene.
- the tumor is selected from the group consisting of acute lymphocytic leukemia, lung cancer, glioma, prostate cancer, colorectal cancer, gastric cancer, liver cancer, esophageal cancer, colorectal cancer, malignant lymphoma, cervical cancer, nasopharyngeal cancer, and breast cancer.
- skin cancer, bladder cancer especially acute lymphoblastic leukemia, lung cancer, glioma, prostate cancer, colorectal cancer with high expression of PAICS.
- the pharmaceutically acceptable derivative of the above compound has the same core structure as the compound itself, and undergoes hydrolysis or the like in the body to form a molecule having the same or similar activity as the original compound, achieving the same or similar therapeutic effects.
- a pharmaceutically acceptable derivative of a compound especially a simple derivative thereof, particularly one of a lower ester, a lower ether, a lower alkyl substituent, a pharmaceutically acceptable salt, or a lower amide, that is, having 1 to 6 carbon atoms. It is preferably a derivative obtained by condensing a carboxylic acid, an alcohol or an amine of 2 to 6, 2 to 4 with a parent compound.
- compositions of the compounds can be synthesized from the parent compound by conventional chemical methods, such as in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: The method described in 3-90639-026-8, Hardcover, 388 pages, August 2002.
- these salts can be prepared by reacting the free base of the compound with an acid in water or an organic solvent or a mixture of the two; usually, a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile is used. .
- Acid addition salts can be prepared by various acids (mineral acids and organic acids).
- the acid addition salt include a salt made of an acid selected from the group consisting of acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (e.g., L-ascorbic acid), and L-aspartate.
- benzenesulfonic acid benzoic acid, 4-acetamidobenzoic acid, butyric acid, (+) camphoric acid, camphor-sulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, citric acid, hexanoic acid, Octanoic acid, cinnamic acid, citric acid, cyclaic acid, lauryl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethylsulfonic acid, formic acid, fumaric acid, galactose Acid, gentisic acid, glucoheptonic acid, D-gluconic acid, glucuronic acid (such as D-glucuronic acid), glutamic acid (such as L-glutamic acid), ⁇ -ketoglutaric acid, glycolic acid, Hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isethionate
- Figure 1 is a three-dimensional solid ribbon structure diagram of PAICS
- FIG. 2 is a diagram showing the interaction of CAIR and SAICAR synthetase in crystal structure, in which A: PDB access ID 2GQS; B: PDB access ID 2CNQ; C: PDB access ID 4FE2;
- Figure 3 is a result of alignment of different SAICAR synthase protein sequences.
- the human PAICS protein sequence has a total length of 425 amino acid residues, of which 2 to 260AA is the SAICAR synthetase domain, 267-425 is the AIR carboxylase domain, and the two domains are linked by the 6-peptide (KSESQC).
- KSESQC 6-peptide 6-peptide
- the GLN159-GLN183 alpha helix of the SAICAR Synthetase domain interacts with the ASN395-ASN424 alpha helix of the AIR carboxylase domain, as shown in Figure 1.
- the structure containing CAIR in the composite has 2GQS, 2CNQ and 4FE2
- the structure containing ASP has 2CNV, 2CNU and 4FE2.
- the tumor is a tumor having a Warburg effect, a high expression of the oncogene myc, a high expression of PAICS, a correlation with Erk1/2, and a high expression of the PKM2 gene.
- the tumor is selected from the group consisting of acute lymphocytic leukemia, lung cancer, glioma, prostate cancer, colorectal cancer, gastric cancer, liver cancer, esophageal cancer, colorectal cancer, malignant lymphoma, cervical cancer, nasopharyngeal cancer, and breast cancer.
- skin cancer, bladder cancer especially acute lymphoblastic leukemia, lung cancer, glioma, prostate cancer, colorectal cancer with high expression of PAICS.
- the pharmaceutically acceptable derivative of the above compound has the same core structure as the compound itself, and undergoes hydrolysis or the like in the body to form a molecule having the same or similar activity as the original compound, achieving the same or similar therapeutic effects.
- a pharmaceutically acceptable derivative of a compound especially a simple derivative thereof, particularly one of a lower ester, a lower ether, a lower alkyl substituent, a pharmaceutically acceptable salt, or a lower amide, that is, having 1 to 6 carbon atoms. It is preferably a derivative obtained by condensing a carboxylic acid, an alcohol or an amine of 2 to 6, 2 to 4 with a parent compound.
- compositions of the compounds can be synthesized from the parent compound by conventional chemical methods, such as in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: The method described in 3-90639-026-8, Hardcover, 388 pages, August 2002.
- these salts can be prepared by reacting the free base of the compound with an acid in water or an organic solvent or a mixture of the two; usually, a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile is used. .
- Acid addition salts can be prepared by various acids (mineral acids and organic acids).
- the acid addition salt include a salt made of an acid selected from the group consisting of acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (e.g., L-ascorbic acid), and L-aspartate.
- benzenesulfonic acid benzoic acid, 4-acetamidobenzoic acid, butyric acid, (+) camphoric acid, camphor-sulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, citric acid, hexanoic acid, Octanoic acid, cinnamic acid, citric acid, cyclaic acid, lauryl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethylsulfonic acid, formic acid, fumaric acid, galactose Acid, gentisic acid, glucoheptonic acid, D-gluconic acid, glucuronic acid (such as D-glucuronic acid), glutamic acid (such as L-glutamic acid), ⁇ -ketoglutaric acid, glycolic acid, Hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isethionate
- Combination therapy can improve the efficacy and reduce side effects.
- two, three, four, five or more compounds or derivatives thereof can be used simultaneously as an active ingredient for treating tumors.
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Abstract
一种干扰SAICAR合成酶活性化合物的应用。基于现有的蛋白结构数据、小分子结构数据,使用软件计算分析,筛选得到可以有效干扰PAICS活性的化合物,使用后可以减少SAICAR的合成,达到治疗或改善肿瘤的目的。通过联合使用化合物中的至少两种,有望获得更佳的治疗或改善肿瘤的效果。
Description
本发明涉及干扰SAICAR合成酶活性化合物的应用。
癌细胞的一个重要的标志是代谢重编程,包括提高葡萄糖摄取和非氧依赖的乳酸发酵,也常被称为沃伯格效应(Warburg effect)[1,2]。这种重新编程对于肿瘤的生长和存活是必要,特别是外界低氧等压力条件下。然而,对于肿瘤细胞代谢重整与肿瘤快速增殖、分化、迁移等相关性的重要分子机制以及作用方式仍然不清楚。
丙酮酸激酶同工酶2(Pyruvate kinase isoform M2,PKM2)作为一个代谢过程中重要的酶在快速增殖和多数肿瘤细胞中高表达,且对肿瘤细胞的代谢和生长影响巨大[3,4]。此外,针对PKM2酶活性的各种药理试剂影响细胞生长和增殖[5,6],这也提示通过靶向PKM2的酶活性为代表,进一步改变肿瘤代谢的方式成为肿瘤治疗的一种新途径[7]。
嘌呤合成代谢是生物体普遍存在而又十分重要的生物代谢,其产物AMP和GMP不仅为生物体内DNA和RNA的生物合成提供原料,而且也为体内许多关键的辅酶(NAD、NADP、FAD和CoA)、信号分子(如cAMP)和重要的能量分子ATP提供其合成所必需的嘌呤碱基。可见,嘌呤合成代谢在整个代谢网络中处于核心位置。嘌呤合成包括从头合成(de novo purine synthesis)和补救途径(salvage pathway)两个合成途径。
在腺嘌呤从头合成的代谢途径中,腺苷酸琥珀酸裂解酶(以下简称ADSL酶)主要参与将SAICAR裂解催化形成AICAR以及S-AMP生成AMP的反应[Spiegel,E.K.,Colman,R.F.,and Patterson,D.(2006).Adenylosuccinate lyase deficiency.Mol Genet Metab 89,19-31.Clamadieu,C.,Cottin,X.,Rousselle,C.,and Claris,O.(2008).Adenylosuccinate lyase deficiency:an unusual cause of neonatal seizure.Arch Pediatr l5,135-138.Castro,M.,Perez-Cerda,C.,Merinero,B.,Garcia,M.J.,Bernar,J.,Gil Nagel,A.,Torres,J.,Bermudez,M.,Garavito,P.,Marie,S.,et al.(2002).Screening for adenylosuccinate lyase deficiency:clinical,biochemical and molecular findings in four patients.Neuropediatrics 33,186-189.]。
在人体中腺嘌呤从头合成代谢途径中代谢酶的异常,往往导致中间有害的代谢产物5-氨基-4-琥珀酸甲酰胺咪唑核糖核苷酸(succiny1-5-aminoimidazole-4-carboxamide-1-ribose-50-phosphate,SAICAR)的累积,在临床上表现为自闭、癫痫、张力减退、发育不良等症状[8-10]。SAICAR合成酶由基因PAICS(phosphoribosylaminoimidazolesuccinocarboxamide synthase)编码,在体内负责SAICAR的合成。相关的研究报道,PAICS高表达于急性淋巴细胞性白血病,肺癌,神经胶质瘤、前列腺癌以及结直肠癌中,并可以作为III期结直肠癌的一个预后标记[11-13]。近期研究发现,在葡萄糖受限的条件下高度积累SAICAR,从而改变了肿瘤细胞中能量水平、糖摄取和乳酸的产生,而这些现象并未发生在成人表皮细胞以及肺成纤 维细胞中[14,15]。SAICAR能够诱导PKM2的酶活性,促进肿瘤细胞的存活[14],而且SAICAR-PKM2的结合能够诱导Erk1/2的磷酸化,高浓度的SAICAR也可诱导癌基因myc的上调表达[15],这些由于腺嘌呤从头合成代谢途径中异常积累的SAICAR促进肿瘤细胞的增殖和存活。
氨基咪唑琥珀基氨甲酰核苷酸合成酶/氨基咪唑核苷酸羧化酶,即PAICS(phosphoribosylaminoimidazole succinocarboxamide synthetase /phosphoribosylaminoimidazole carboxylase)是一种嘌呤从头合成途径中重要的双功能酶,它具有SAICAR合成酶(4-(N-succinylcarboxamide)-5-aminoimidazole ribonucleotide synthetase,SAICARs)和AIR羧化酶(5-aminoimidazole ribonucleotide carboxylase,AIRc)的功能,催化嘌呤从头合成代谢第六步、第七步反应,其中的一个关键反应过程如下所示
所以,对于异常高表达PAICS的肿瘤常常会伴随着有害代谢产物SAICAR的积累,而针对抑制PAICS的表达或其酶活性的研究将成为肿瘤治疗的新手段。开发或筛选出可以有效抑制PAICS活性的化合物,具有非常重要的意义。
参见文献:
1.Hanahan,D.and R.A.Weinberg,Hallmarks of cancer:the next generation.Cell,2011.144(5):p.646-74.
2.Hsu,P.P.and D.M.Sabatini,Cancer cell metabolism:Warburg and beyond.Cell,2008.134(5):p.703-7.
3.Christofk,H.R.,et al.,The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth.Nature,2008.452(7184):p.230-3.
4.Wolf,A.,et al.,Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiiforme.J Exp Med,2011.208(2):p.313-26.
5.Chen,J.,et al.,Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2.Oncogene,2011.30(42):p.4297-306.
6.Anastasiou,D.,et al.,Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis.Nat Chem Biol,2012.8(10):p.839-47.
7.Vander Heiden,M.G.,Exploiting tumor metabolism:challenges for clinical translation.J Clin Invest,2013.123(9):p.3648-51.
8.Ciardo,F.,C.Salerno,and P.Curatolo,Neurologic aspects of adenylosuccinate lyase deficiency.J Child Neurol,2001.16(5):p.301-8.
9.Gitiaux,C.,et al.,Misleading behavioural phenotype with adenylosuccinate lyase deficiency.Eur J Hum Genet,2009.17(1):p.133-6.
10.Mierzewska,H.,et al.,Severe encephalopathy with brain atrophy and hypomyelination due to adenylosuccinate lyase deficiency--MRI,clinical,biochemical and neuropathological findings of Polish patients.Folia Neuropathol,2009.47(4):p.314-20.
11.Eissmann,M.,et al.,A fumctional yeast survival screen of tumor-derived cDNA libraries designed to identify anti-apoptotic mammalian oncogenes.PLoS One,2013.8(5):p.e64873.
12.Goswami,M.T.,et al.,Role and regulation of coordinately expressed de novo purine biosynthetic enzymes PPAT and PAICS in lung cancer.Oncotarget,2015.6(27):p.23445-61.
13.Chakravarthi,B.V.,et al.,Expression and Role of PAICS,a De Novo Purine Biosynthetic Gene in Prostate Cancer.Prostate,2017.77(1):p.10-21.
14.Keller,K.E.,I.S.Tan,and Y.S.Lee,SAICAR stimulates pyruvate kinase isoform M2 and promotes cancer cell survival in glucose-limited conditions.Science,2012.338(6110):p.1069-72.
15.Keller,K.E.,et al.,SAICAR induces protein kinase activity of PKM2 that is necessary for sustained proliferative signaling of cancer cells.Mol Cell,2014.53(5):p.700-9。
发明内容
本发明的目的在于提供干扰SAICAR合成酶活性化合物的应用。
发明人基于现有的蛋白结构数据、小分子结构数据,使用软件计算分析,发现DrugBankID为DB00863、DB05800、DB00585、DB00303、DB00710、DB00451、DB00143、DB01102、DB01255、DB01040、DB00983、DB04983、DB00923、DB05630、DB01661、DB01868、DB02578、DB02696、DB02716、DB02738、DB03287、DB03536、DB03820、DB04022、DB04083、DB04366、DB04488、DB04517、DB03664、DB03845、DB03280、DB03222、DB03909、DB01717、DB02181、DB03725、DB04158、DB03483、DB02887、DB03755、DB01860、DB04005、DB04395、DB02333、DB02452、DB02431、DB02189、DB03797、DB04204、DB03931、DB04362、DB03557、DB03853、DB04023、DB02836、DB03258、DB01660、DB04121、DB03532、DB04728、DB03148、DB03041、DB01649、DB02596、DB02355、DB04264、DB02082、DB02554、DB03186、DB03004、DB03907、DB01773、DB01658、DB03958、DB03361、DB03358、DB03126、DB04099、DB01690、DB04497、DB02814、DB03491、DB01842、DB02363、DB03639、DB01821、DB04700、DB02927、DB02267、DB04633、DB04207、DB03433、DB03003、DB01910、DB01813、DB02011、DB03327、DB02075、DB02077、DB01815、DB01974、DB04323、DB03927、DB03582、DB02537、DB01634、DB04153、DB04649、DB04778、DB02824、DB04701、DB01657、DB02941、DB04684、DB02492、DB03427、DB03686、DB04762、DB03602、DB04808、DB04341、 DB01895、DB03624、DB04434、DB04602的化合物,可以有效干扰PAICS的活性,进而减少SAICAR的合成,达到治疗或改善肿瘤的目的。
肿瘤为具有沃伯格效应、癌基因myc高表达、PAICS高表达、与Erk1/2相关和PKM2基因高表达中任一种特性的肿瘤。特别的,肿瘤选自急性淋巴细胞性白血病、肺癌、神经胶质瘤、前列腺癌、结直肠癌、胃癌、肝癌、食管癌、大肠癌、恶性淋巴瘤、子宫颈癌、鼻咽癌、乳腺癌、皮肤癌、膀胱癌,特别是PAICS高表达的急性淋巴细胞性白血病、肺癌、神经胶质瘤、前列腺癌、结直肠癌。
上述化合物药学上可接受的衍生物,具有与化合物本身相同的母核结构,在体内经过水解等作用,可以生成与原化合物具有相同或相近活性的分子,达到相同或相近的治疗效果。
化合物药学上可接受的衍生物,尤其指其简单衍生物,特别是其低级酯、低级醚、低级烷基取代物、药用盐、低级酰胺中的一种,即碳原子数在1~6,优选为2~6,2~4的羧酸、醇、胺与母化合物缩合得到的衍生物。
化合物药学上可接受的药用盐可以通过常规的化学方法从母体化合物合成,如在Pharmaceutical Salts:Properties,Selection,and Use,P.Heinrich Stahl(Editor),Camille G.Wermuth(Editor),ISBN:3-90639-026-8,Hardcover,388pages,August 2002中描述的方法。一般来说,这些盐可以由化合物的游离碱和酸在水或有机溶剂或二者的混合液中反应制得;通常,使用非水介质如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈。
酸加成盐可以通过各种酸(无机酸和有机酸)制得。酸加成盐的实例包括由酸制成的盐,所述酸选自由乙酸、2,2-二氯乙酸、已二酸、藻酸、抗坏血酸(如L-抗坏血酸)、L-天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、丁酸、(+)樟脑酸、樟脑-磺酸、(+)-(1S)-樟脑-10-磺酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环拉酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟乙基磺酸、甲酸、富马酸、半乳糖酸、龙胆酸、葡庚糖酸、D-葡萄糖酸、葡萄糖醛酸(如D-葡萄糖醛酸)、谷氨酸(如L-谷氨酸)、α-酮戊二酸、乙醇酸、马尿酸、氢溴酸、盐酸、氢碘酸、羟乙磺酸、(+)-L-乳酸、(±)-DL-乳酸、乳糖酸、马来酸、苹果酸、(-)-L-苹果酸、丙二酸、(±)-DL-扁桃酸、甲基磺酸、萘-2-磺酸、萘-1,5-二磺酸、1-羟基-2-萘酸、烟酸、硝酸、油酸、乳清酸、草酸、棕榈酸、帕莫酸、磷酸、丙酸、L-焦谷氨酸、水杨酸、4-氨基-水杨酸、癸二酸、硬脂酸、丁二酸、硫酸、单宁酸、(+)-L-酒石酸、硫氰酸、p-甲苯磺酸、十一碳烯酸和戊酸,以及酰化氨基酸组成的组。
通过联合使用上述化合物中的至少两种,有望获得更佳的治疗或改善肿瘤的效果。
图1是PAICS的三维彩带(solid ribbon)结构图;
图2是CAIR和SAICAR合成酶在晶体结构中的相互作用图,图中A:PDB access ID 2GQS;B:PDB access ID 2CNQ;C:PDB access ID 4FE2;
图3是不同种SAICAR合成酶蛋白序列对齐结果。
人PAICS蛋白质序列全长425个氨基酸残基,其中2~260AA为SAICAR synthetase结构域,267-425为AIR carboxylase结构域,两结构域由6肽(KSESQC)连接。此外,SAICAR Synthetase结构域的GLN159~GLN183 α螺旋和AIR carboxylase结构域的ASN395~ASN424 α螺旋相互作用,紧密结合这一起,如图1所示。
在蛋白质结构数据库中(RCSB),收录了不同来源的SAICAR synthetase晶体结构数据,其中包括Saccharomyces cerevisiae(1A48,2CNQ,2CNV,2CNU,1OBD,1OBG)、Pyrococcus horikoshii OT3(3U54,3U55)、Escherichia coli(2GQR,2GQS)、Methanocaldococcus jannaschii(2YZL,2Z02)、Streptococcus pneumonia(4FGR,4FE2)、Mycobacterium abscessus ATCC 19977/DSM 44196(3R9R)、Thermotoga maritime(1KUT)、Clostridium perfringens(3NUA)、Ehrlichia chaffeensis(3KRE)、Geobacillus kaustophilus(2YWV)。以及PAICS晶体结构数据Homo sapiens(2H31)和Bombyx mori(4JA0)。其中复合物中含有CAIR的结构有2GQS、2CNQ和4FE2,含有ASP的结构有2CNV、2CNU和4FE2。
如图2,在2CNQ中CAIR
以内的残基Arg122、Ser128、ASP215、Arg242和Arg264;2GQS中CAIR
以内的残基Arg94、Ser100、ASP129、ASP175、Arg199和Arg215;4FE2中CAIR 3埃以内的残基Arg93、Ser99、ASP174、Arg199、Arg214。对照不同物种来源的SAICAR蛋白序列对齐结果(图3),可以看出不同物种SAICAR synthetase与CAIR的结合呈现高度保守性,主要以氢键作用固定CAIR。
基于以上结果,同时考虑到人的PAICS晶体结构中没有结合CAIR的构象,催化区域没有形成催化构象。进行计算筛选得到的结果不可靠。因此采用Saccharomyces cerevisiae(PDB:2CNQ)和Escherichia coli(PDB:2GQS)SAICAR合成酶晶体结构中的构象作为计算筛选的受体结构。采用Discovery studio的ligand fit模块,对DrugBank(http://www.drugbank.ca/downloads#structures)中的4661种小分子药物进行计算筛选。按对接得分排序,选取前500个构象,剔除重复后,得到的重点筛选结果如表1所示。
表1、计算筛选结果
经过生化酶活实验、细胞生物学实验确证,化合物对SAICAR的蓄积抑制率以及其抗癌有效性(+越多,代表其有效性越强)如下:
上述计算机筛选结果和实验数据表明表中的化合物(DB00863、DB05800、DB00585、DB00303、DB00710、DB00451、DB00143、DB01102、DB01255、DB01040、DB00983、DB04983、DB00923、DB05630、DB01661、DB01868、DB02578、DB02696、DB02716、DB02738、DB03287、DB03536、DB03820、DB04022、DB04083、DB04366、DB04488、DB04517、DB03664、DB03845、DB03280、DB03222、DB03909、DB01717、 DB02181、DB03725、DB04158、DB03483、DB02887、DB03755、DB01860、DB04005、DB04395、DB02333、DB02452、DB02431、DB02189、DB03797、DB04204、DB03931、DB04362、DB03557、DB03853、DB04023、DB02836、DB03258、DB01660、DB04121、DB03532、DB04728、DB03148、DB03041、DB01649、DB02596、DB02355、DB04264、DB02082、DB02554、DB03186、DB03004、DB03907、DB01773、DB01658、DB03958、DB03361、DB03358、DB03126、DB04099、DB01690、DB04497、DB02814、DB03491、DB01842、DB02363、DB03639、DB01821、DB04700、DB02927、DB02267、DB04633、DB04207、DB03433、DB03003、DB01910、DB01813、DB02011、DB03327、DB02075、DB02077、DB01815、DB01974、DB04323、DB03927、DB03582、DB02537、DB01634、DB04153、DB04649、DB04778、DB02824、DB04701、DB01657、DB02941、DB04684、DB02492、DB03427、DB03686、DB04762、DB03602、DB04808、DB04341、DB01895、DB03624、DB04434、DB04602)均可以有效与PAICS作用,影响SAICAR的合成,有望开发为肿瘤治疗药物或保健品。肿瘤为具有沃伯格效应、癌基因myc高表达、PAICS高表达、与Erk1/2相关和PKM2基因高表达中任一种特性的肿瘤。特别的,肿瘤选自急性淋巴细胞性白血病、肺癌、神经胶质瘤、前列腺癌、结直肠癌、胃癌、肝癌、食管癌、大肠癌、恶性淋巴瘤、子宫颈癌、鼻咽癌、乳腺癌、皮肤癌、膀胱癌,特别是PAICS高表达的急性淋巴细胞性白血病、肺癌、神经胶质瘤、前列腺癌、结直肠癌。
上述化合物药学上可接受的衍生物,具有与化合物本身相同的母核结构,在体内经过水解等作用,可以生成与原化合物具有相同或相近活性的分子,达到相同或相近的治疗效果。
化合物药学上可接受的衍生物,尤其指其简单衍生物,特别是其低级酯、低级醚、低级烷基取代物、药用盐、低级酰胺中的一种,即碳原子数在1~6,优选为2~6,2~4的羧酸、醇、胺与母化合物缩合得到的衍生物。
化合物药学上可接受的药用盐可以通过常规的化学方法从母体化合物合成,如在Pharmaceutical Salts:Properties,Selection,and Use,P.Heinrich Stahl(Editor),Camille G.Wermuth(Editor),ISBN:3-90639-026-8,Hardcover,388pages,August 2002中描述的方法。一般来说,这些盐可以由化合物的游离碱和酸在水或有机溶剂或二者的混合液中反应制得;通常,使用非水介质如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈。
酸加成盐可以通过各种酸(无机酸和有机酸)制得。酸加成盐的实例包括由酸制成的盐,所述酸选自由乙酸、2,2-二氯乙酸、己二酸、藻酸、抗坏血酸(如L-抗坏血酸)、L-天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、丁酸、(+)樟脑酸、樟脑-磺酸、(+)-(1S)-樟脑-10-磺酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环拉酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟乙基磺酸、甲酸、富马酸、半乳糖酸、龙胆酸、葡庚糖酸、D-葡萄糖酸、葡萄糖醛酸(如D-葡萄糖醛酸)、谷氨酸(如L-谷氨酸)、α-酮戊二酸、乙醇酸、马尿酸、氢溴酸、盐酸、氢碘酸、羟乙磺酸、(+)-L-乳酸、(±)-DL-乳酸、乳糖酸、马来酸、苹果酸、(-)-L-苹果酸、丙二酸、(±)-DL-扁桃酸、甲基磺酸、萘-2-磺酸、萘-1,5-二磺酸、1-羟基-2-萘酸、 烟酸、硝酸、油酸、乳清酸、草酸、棕榈酸、帕莫酸、磷酸、丙酸、L-焦谷氨酸、水杨酸、4-氨基-水杨酸、癸二酸、硬脂酸、丁二酸、硫酸、单宁酸、(+)-L-酒石酸、硫氰酸、p-甲苯磺酸、十一碳烯酸和戊酸,以及酰化氨基酸组成的组。
组合用药在一定程度上可以提高疗效,减少毒副作用。优选的,可以同时使用2种、3种、4种、5种或更多种化合物或其衍生物作为治疗肿瘤的活性成分。
Claims (21)
- 化合物或其药学上可接受的衍生物在制备SAICAR合成酶活性干扰剂或抑制剂中的应用,其中,化合物的DrugBank ID为DB00863、DB05800、DB00585、DB00303、DB00710、DB00451、DB00143、DB01102、DB01255、DB01040、DB00983、DB04983、DB00923、DB05630、DB01661、DB01868、DB02578、DB02696、DB02716、DB02738、DB03287、DB03536、DB03820、DB04022、DB04083、DB04366、DB04488、DB04517、DB03664、DB03845、DB03280、DB03222、DB03909、DB01717、DB02181、DB03725、DB04158、DB03483、DB02887、DB03755、DB01860、DB04005、DB04395、DB02333、DB02452、DB02431、DB02189、DB03797、DB04204、DB03931、DB04362、DB03557、DB03853、DB04023、DB02836、DB03258、DB01660、DB04121、DB03532、DB04728、DB03148、DB03041、DB01649、DB02596、DB02355、DB04264、DB02082、DB02554、DB03186、DB03004、DB03907、DB01773、DB01658、DB03958、DB03361、DB03358、DB03126、DB04099、DB01690、DB04497、DB02814、DB03491、DB01842、DB02363、DB03639、DB01821、DB04700、DB02927、DB02267、DB04633、DB04207、DB03433、DB03003、DB01910、DB01813、DB02011、DB03327、DB02075、DB02077、DB01815、DB01974、DB04323、DB03927、DB03582、DB02537、DB01634、DB04153、DB04649、DB04778、DB02824、DB04701、DB01657、DB02941、DB04684、DB02492、DB03427、DB03686、DB04762、DB03602、DB04808、DB04341、DB01895、DB03624、DB04434、DB04602。
- 根据权利要求1所述的应用,其特征在于:SAICAR合成酶为PAICS。
- 根据权利要求1所述的应用,其特征在于:化合物药学上可接受的衍生物为其简单衍生物。
- 根据权利要求3所述的应用,其特征在于:简单衍生物为其低级酯、低级醚、低级烷基取代物、药用盐、低级酰胺中的一种。
- 化合物或其药学上可接受的衍生物在制备肿瘤治疗或缓解药物,或有益肿瘤的保健品中的应用,其中,化合物的DrugBank ID为DB00863、DB05800、DB00585、DB00303、DB00710、DB00451、DB00143、DB01102、DB01255、DB01040、DB00983、DB04983、DB00923、DB05630、DB01661、DB01868、DB02578、DB02696、DB02716、DB02738、DB03287、DB03536、DB03820、DB04022、DB04083、DB04366、DB04488、DB04517、DB03664、DB03845、DB03280、DB03222、DB03909、DB01717、DB02181、DB03725、DB04158、DB03483、DB02887、DB03755、DB01860、DB04005、DB04395、DB02333、DB02452、DB02431、DB02189、DB03797、DB04204、DB03931、DB04362、DB03557、DB03853、DB04023、DB02836、DB03258、DB01660、DB04121、DB03532、DB04728、DB03148、DB03041、DB01649、DB02596、DB02355、DB04264、DB02082、DB02554、DB03186、DB03004、DB03907、DB01773、DB01658、DB03958、DB03361、DB03358、DB03126、DB04099、DB01690、DB04497、DB02814、DB03491、DB01842、DB02363、DB03639、DB01821、DB04700、DB02927、 DB02267、DB04633、DB04207、DB03433、DB03003、DB01910、DB01813、DB02011、DB03327、DB02075、DB02077、DB01815、DB01974、DB04323、DB03927、DB03582、DB02537、DB01634、DB04153、DB04649、DB04778、DB02824、DB04701、DB01657、DB02941、DB04684、DB02492、DB03427、DB03686、DB04762、DB03602、DB04808、DB04341、DB01895、DB03624、DB04434、DB04602。
- 根据权利要求5所述的应用,其特征在于:化合物药学上可接受的衍生物为其简单衍生物。
- 根据权利要求6所述的应用,其特征在于:简单衍生物为其低级酯、低级醚、低级烷基取代物、药用盐、低级酰胺中的一种。
- 根据权利要求5~7任意一项所述的应用,其特征在于:肿瘤为具有沃伯格效应、癌基因myc高表达、PAICS高表达、与Erk1/2相关和PKM2基因高表达中任一种特性的肿瘤。
- 根据权利要求5~7任意一项所述的应用,其特征在于:肿瘤选自急性淋巴细胞性白血病、肺癌、神经胶质瘤、前列腺癌、结直肠癌、胃癌、肝癌、食管癌、大肠癌、恶性淋巴瘤、子宫颈癌、鼻咽癌、乳腺癌、皮肤癌、膀胱癌。
- 一种治疗或缓解肿瘤的组合物,其特征在于:其活性成分选自DrugBank ID为DB00863、DB05800、DB00585、DB00303、DB00710、DB00451、DB00143、DB01102、DB01255、DB01040、DB00983、DB04983、DB00923、DB05630、DB01661、DB01868、DB02578、DB02696、DB02716、DB02738、DB03287、DB03536、DB03820、DB04022、DB04083、DB04366、DB04488、DB04517、DB03664、DB03845、DB03280、DB03222、DB03909、DB01717、DB02181、DB03725、DB04158、DB03483、DB02887、DB03755、DB01860、DB04005、DB04395、DB02333、DB02452、DB02431、DB02189、DB03797、DB04204、DB03931、DB04362、DB03557、DB03853、DB04023、DB02836、DB03258、DB01660、DB04121、DB03532、DB04728、DB03148、DB03041、DB01649、DB02596、DB02355、DB04264、DB02082、DB02554、DB03186、DB03004、DB03907、DB01773、DB01658、DB03958、DB03361、DB03358、DB03126、DB04099、DB01690、DB04497、DB02814、DB03491、DB01842、DB02363、DB03639、DB01821、DB04700、DB02927、DB02267、DB04633、DB04207、DB03433、DB03003、DB01910、DB01813、DB02011、DB03327、DB02075、DB02077、DB01815、DB01974、DB04323、DB03927、DB03582、DB02537、DB01634、DB04153、DB04649、DB04778、DB02824、DB04701、DB01657、DB02941、DB04684、DB02492、DB03427、DB03686、DB04762、DB03602、DB04808、DB04341、DB01895、DB03624、DB04434、DB04602的化合物中,或其药学上可接受的衍生物中的至少两种。
- 根据权利要求10所述的组合物,其特征在于:其活性成分选自DrugBank ID为DB00863、DB05800、DB00585、DB00303、DB00710、DB00451、DB00143、DB01102、DB01255、DB01040、DB00983、 DB04983、DB00923、DB05630、DB01661、DB01868、DB02578、DB02696、DB02716、DB02738、DB03287、DB03536、DB03820、DB04022、DB04083、DB04366、DB04488、DB04517、DB03664、DB03845、DB03280、DB03222、DB03909、DB01717、DB02181、DB03725、DB04158、DB03483、DB02887、DB03755、DB01860、DB04005、DB04395、DB02333、DB02452、DB02431、DB02189、DB03797、DB04204、DB03931、DB04362、DB03557、DB03853、DB04023、DB02836、DB03258、DB01660、DB04121、DB03532、DB04728、DB03148、DB03041、DB01649、DB02596、DB02355、DB04264、DB02082、DB02554、DB03186、DB03004、DB03907、DB01773、DB01658、DB03958、DB03361、DB03358、DB03126、DB04099、DB01690、DB04497、DB02814、DB03491、DB01842、DB02363、DB03639、DB01821、DB04700、DB02927、DB02267、DB04633、DB04207、DB03433、DB03003、DB01910、DB01813、DB02011、DB03327、DB02075、DB02077、DB01815、DB01974、DB04323、DB03927、DB03582、DB02537、DB01634、DB04153、DB04649、DB04778、DB02824、DB04701、DB01657、DB02941、DB04684、DB02492、DB03427、DB03686、DB04762、DB03602、DB04808、DB04341、DB01895、DB03624、DB04434、DB04602的化合物中,或其药学上可接受的衍生物中的至少3种。
- 根据权利要求10或11所述的组合物,其特征在于:化合物药学上可接受的衍生物为其简单衍生物。
- 根据权利要求12所述的组合物,其特征在于:简单衍生物为其低级酯、低级醚、低级烷基取代物、药用盐、低级酰胺中的一种。
- 根据权利要求10~13所述的组合物,其特征在于:组合物还包括药学或食品上可接受的辅料。
- 根据权利要求10~14所述的组合物,其特征在于:肿瘤为具有沃伯格效应、癌基因myc高表达、PAICS高表达、与Erk1/2相关和PKM2基因高表达中任一种特性的肿瘤。
- 根据权利要求10~14所述的组合物,其特征在于:肿瘤选自急性淋巴细胞性白血病、肺癌、神经胶质瘤、前列腺癌、结直肠癌、胃癌、肝癌、食管癌、大肠癌、恶性淋巴瘤、子宫颈癌、鼻咽癌、乳腺癌、皮肤癌、膀胱癌。
- 治疗或缓解肿瘤的方法,包括给予患者治疗量的化合物或其药学上可接受的衍生物,其中,化合物的DrugBank ID为DB00863、DB05800、DB00585、DB00303、DB00710、DB00451、DB00143、DB01102、DB01255、DB01040、DB00983、DB04983、DB00923、DB05630、DB01661、DB01868、DB02578、DB02696、DB02716、DB02738、DB03287、DB03536、DB03820、DB04022、DB04083、DB04366、DB04488、DB04517、DB03664、DB03845、DB03280、DB03222、DB03909、DB01717、DB02181、DB03725、DB04158、DB03483、DB02887、DB03755、DB01860、DB04005、DB04395、DB02333、DB02452、DB02431、DB02189、DB03797、DB04204、DB03931、DB04362、DB03557、DB03853、DB04023、DB02836、DB03258、DB01660、DB04121、DB03532、DB04728、DB03148、DB03041、 DB01649、DB02596、DB02355、DB04264、DB02082、DB02554、DB03186、DB03004、DB03907、DB01773、DB01658、DB03958、DB03361、DB03358、DB03126、DB04099、DB01690、DB04497、DB02814、DB03491、DB01842、DB02363、DB03639、DB01821、DB04700、DB02927、DB02267、DB04633、DB04207、DB03433、DB03003、DB01910、DB01813、DB02011、DB03327、DB02075、DB02077、DB01815、DB01974、DB04323、DB03927、DB03582、DB02537、DB01634、DB04153、DB04649、DB04778、DB02824、DB04701、DB01657、DB02941、DB04684、DB02492、DB03427、DB03686、DB04762、DB03602、DB04808、DB04341、DB01895、DB03624、DB04434、DB04602。
- 根据权利要求17所述的方法,其特征在于:化合物药学上可接受的衍生物为其简单衍生物。
- 根据权利要求18所述的方法,其特征在于:简单衍生物为其低级酯、低级醚、低级烷基取代物、药用盐、低级酰胺中的一种。
- 根据权利要求17~19所述的方法,其特征在于:肿瘤为具有沃伯格效应、癌基因myc高表达、PAICS高表达、与Erk1/2相关和PKM2基因高表达中任一种特性的肿瘤。
- 根据权利要求17~19所述的方法,其特征在于:肿瘤选自急性淋巴细胞性白血病、肺癌、神经胶质瘤、前列腺癌、结直肠癌、胃癌、肝癌、食管癌、大肠癌、恶性淋巴瘤、子宫颈癌、鼻咽癌、乳腺癌、皮肤癌、膀胱癌。
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