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WO2019033257A1 - Nouvelle utilisation de composé interférant avec l'activité de la saicar synthétase - Google Patents

Nouvelle utilisation de composé interférant avec l'activité de la saicar synthétase Download PDF

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WO2019033257A1
WO2019033257A1 PCT/CN2017/097467 CN2017097467W WO2019033257A1 WO 2019033257 A1 WO2019033257 A1 WO 2019033257A1 CN 2017097467 W CN2017097467 W CN 2017097467W WO 2019033257 A1 WO2019033257 A1 WO 2019033257A1
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acid
compound
pharmaceutically acceptable
cancer
derivative
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PCT/CN2017/097467
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English (en)
Chinese (zh)
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孙奋勇
潘武广
朱威
赵德志
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广州君赫生物科技有限公司
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Publication of WO2019033257A1 publication Critical patent/WO2019033257A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof

Definitions

  • the present invention relates to compounds and novel uses thereof, and in particular to compounds and their use in the preparation of SAICAR synthetase activity interferences or inhibitors.
  • Adenyl succinate lyase deficiency (adenylosuccinatelyase deficiency ADSL deficiency) is a metabolic disorder in which adenine de novo synthesis and purine nucleotide metabolism pathways produce deletions and disorders.
  • the cause of the disease is mainly due to mutation or deletion of adenyl succinate lyase in the patient, resulting in excessive accumulation of the enzyme substrate SAICAR in the cell without timely clearance [Jaeken J, Van den Berghe G. (1984). An infantile autistic syndrome characterized by the presence of succinylpurines in body fluids. Lancet 8411: 1058-1061.].
  • Adenylosuccinatelyase deficiency an unusual cause of neonatal seizure.
  • Arch Pediatr 15 135-138.
  • Screening for adenylosuccinatelyase deficiency clinical, biochemical and molecular findings in four patients. Neuropediatrics 33, 186-189.
  • ADSL deficiency has three consecutive major phenotypes: neonatal lethal, severe (type I) and mild to moderate (type II). It has been clinically found that even patients from the same family have different phenotypes. The onset is generally seen in the period from birth to infancy. The reported cases have fatal neonatal brain lesions (expressed with motor dysfunction, refractory epilepsy, respiratory disorders), moderate mental retardation. All patients have mental retardation, most of them have different types of epilepsy, and about one-third of them have autistic features (no eye contact, sensitivity to sound and light, repetitive behavior, agitation, temper tantrum, self-injury and Self-mutilation).
  • Other uncommon clinical manifestations include delayed mental activity, hyperactivity, speech disorders, muscle tone loss, muscle atrophy, and paralysis. Severe patients usually have microcephaly. Prenatal clinical manifestations include: intrauterine growth impaired, microcephaly, fetal motor function Decreased and missing fetal heart rate changes.
  • 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.
  • 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
  • Gitiaux, C. Ceballos-Picot, I., Marie ,S.,Valayannopoulos,V,Rio,M.,Verrieres,S.,Benoist,JF,Vincent,MF,Desguerre,I.,and Bahi-Buisson,N.(2009).Misleading behavioural phenotype with adenylosuccinatelyase deficiency.Eur J Hum Genet 17, 133-136. Mierzewska, H., Schmidt-Sidor, B., Jurkiewicz, E., Bogdanska, A., Kusmierska, K., and Stepien, T. (2009).
  • SAICAr is the product of SAICAR dephosphorylation
  • S-Ado is the product of S-AMP dephosphorylation
  • 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.
  • SAICAR can induce the enzymatic activity of PKM2 and promote the survival of tumor cells, and the binding of SAICAR-PKM2 can induce the phosphorylation of Erk1/2.
  • the high concentration of SAICAR can also induce the up-regulation of oncogene myc. These are due to adenine de novo anabolism. Abnormal accumulation of SAICAR in the pathway promotes tumor cell proliferation and survival.
  • PAICS phosphoribosylaminoimidazolesuccinocarboxamidesynthetase/phosphoribosylaminoimidazolecarboxylase
  • SAICAR synthetase (4 -(N-succinylcarboxamide)-5-aminoimidazole ribonucleotidesynthetase, SAICARs) and AIR carboxylase (AIRc) function, catalyze the de novo catabolism of the sixth and seventh steps, one of the key reaction processes As follows
  • the object of the invention is a novel application of the compound to interfere with the activity of SAICAR synthase.
  • the tumor is a tumor having a Warburg effect, a high expression of the oncogene myc, 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, squamous cell carcinoma, gastric cancer, liver cancer, esophageal cancer, colorectal cancer, malignant lymphoma, cervical cancer, nasopharyngeal carcinoma, and breast cancer.
  • skin cancer, bladder cancer especially acute lymphoblastic leukemia, lung cancer, glioma, prostate cancer, and straight cancer.
  • 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 ⁇ helix of the SAICAR Synthetase domain interacts with the ASN395-ASN424 ⁇ 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.
  • DB01864 (5'-Guanosine-Diphosphate-Monothiophosphate) and DB03295 (Glutathionylspermidine) can effectively interact with PAICS, affecting the synthesis of SAICAR, and it is expected to be developed as a tumor treatment drug or health care product.
  • Cellular experimental data showed that the accumulation inhibition rate of compound DB01864 on SAICAR It can reach 28.262%; the accumulation inhibition rate of compound DB03295 for SAICAR can reach 35.3%.
  • the tumor is a tumor having a Warburg effect, a high expression of the oncogene myc, 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, squamous cell carcinoma, gastric cancer, liver cancer, esophageal cancer, colorectal cancer, malignant lymphoma, cervical cancer, nasopharyngeal carcinoma, and breast cancer.
  • skin cancer, bladder cancer especially acute lymphoblastic leukemia, lung cancer, glioma, prostate cancer, and straight cancer.
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
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Abstract

L'invention concerne l'utilisation d'un composé, tel que celui sous ID DB01864 ou DB03295 de la DrugBank, dans la préparation d'un perturbateur ou d'un inhibiteur de l'activité de SAICAR synthétase, dans un médicament de traitement ou de soulagement d'une tumeur, ou dans un médicament de traitement ou de soulagement pour une déficience en ADSL.
PCT/CN2017/097467 2017-08-15 2017-08-15 Nouvelle utilisation de composé interférant avec l'activité de la saicar synthétase WO2019033257A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003037371A2 (fr) * 2001-10-31 2003-05-08 Universite Libre De Bruxelles Agonistes de kinase amp ou promedicaments d'adenosine en tant qu'agents immunostimulants

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003037371A2 (fr) * 2001-10-31 2003-05-08 Universite Libre De Bruxelles Agonistes de kinase amp ou promedicaments d'adenosine en tant qu'agents immunostimulants

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
AGNIESZKA, J. ET AL.: "Adenylosuccinate Lyase Deficiency", J INHERIT METAB DIS, vol. 38, no. 2, 12 August 2014 (2014-08-12), pages 231 - 242, XP035457180 *
DATABASE DrugBank 13 June 2005 (2005-06-13), "5'-Guanosine-Diphosphate-Monothiophosphate", XP055576148, Database accession no. DB01864 *

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