WO2023218306A1 - Activité antitumorale de méso-(p-acétamidophényl)-calix[4]pyrrole par inhibition de l'activité enzymatique de la protéine glycyl-arnt synthase 1 (gars1) - Google Patents

Activité antitumorale de méso-(p-acétamidophényl)-calix[4]pyrrole par inhibition de l'activité enzymatique de la protéine glycyl-arnt synthase 1 (gars1) Download PDF

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WO2023218306A1
WO2023218306A1 PCT/IB2023/054699 IB2023054699W WO2023218306A1 WO 2023218306 A1 WO2023218306 A1 WO 2023218306A1 IB 2023054699 W IB2023054699 W IB 2023054699W WO 2023218306 A1 WO2023218306 A1 WO 2023218306A1
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protein
formula
gars1
glycyl
trna synthase
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PCT/IB2023/054699
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English (en)
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Camillo ROSANO
Franz Heinrich KOHNKE
Giacomo DRAGO
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Giam Pharma International sarl
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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
    • A61K31/40—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
    • A61K31/409—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 having four such rings, e.g. porphine derivatives, bilirubin, biliverdine
    • 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
    • A61K31/40—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
    • A61K31/4025—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 not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention belongs to the field of molecular biology, pharmaceutical chemistry and medicine.
  • it refers to pyrrole compounds, specifically, to calixpyrrole compounds used as inhibitors of the enzymatic activity of the protein Glycyl-tRNA Synthase 1 (GARS1) or in methods of modulation of the enzymatic activity of the protein Glycyl-tRNA Synthase 1 (GARS1), which exhibit antitumor activity in vivo.
  • Calixpyrroles are a class of macrocyclic compounds containing pyrrole units bonded at their 2,5-positions with carbon atoms containing two additional substituents other than hydrogen (usually alkyl and/or aryl groups). Therefore, calixpyrroles differ from porphyrogens in that they are not convertible into porphyrin systems which instead have planar structures and are characterized by extensive electron delocalization.
  • Glycyl-tRNA Synthase 1 (GARS1) protein identified by the code UniProtKB_AC: P42150.
  • the object of the present invention is therefore being able to inhibit the protein Glycyl- tRNA Synthase 1 (GARS1) or to find a method to modulate the activity of the protein Glycyl- tRNA Synthase 1 (GARS1).
  • the present invention faces (and solves) the problem of finding a method to inhibit and/or modulate the activity of the protein Glycyl-tRNA Synthase 1 (GARS1).
  • Glycyl-tRNA Synthase 1 Glycyl-tRNA Synthase 1
  • the present invention solves the aforementioned problem through the use of the pyrrole compound of formula (I) as outlined in the attached claims, the definitions of which are an integral part of the present description, Glycyl-tRNA Synthase 1.
  • the compound (I) allows to inhibit the growth of tumors NSCLC in vivo through inhibition of Glycyl-tRNA Synthase 1 (GARS1) protein activity.
  • Fig. 1 shows the ranking obtained from the in silico screening of a database of 55316 experimentally resolved protein structures (deposited in the public database “RCSB Protein Data Bank” [REF_SP_1]) performed using the SPILLO-PBSS software.
  • the points of the plot correspond to the proteins in decreasing order of score.
  • the GARS1 protein (PDB code: 4KR3 - UniProtKB_AC: P41250) was identified in the first position.
  • Fig. 2 shows the ability of the compound of formula (I) and of formula (II) as described in the present invention to inhibit the enzymatic activity of the protein Glycyl-tRNA Synthase 1 (GARS1).
  • GAS1 Glycyl-tRNA Synthase 1
  • the composition may contain only A; only B; only C; A and B in combination; A and C in combination; B and C in combination; or A, B and C in combination.
  • Glycyl-tRNA Synthase 1 belongs to the enzyme family of aminoacyl- tRNA synthetases that play essential roles in cells, catalyzing the aminoacylation of tRNA substrates, juxtaposing ATP, amino acids, and tRNAs and the aminoacylated tRNAs that are used in synthesis protein from the ribosome.
  • Glycyl-tRNA Synthase 1 plays a critical role in neddylation and upregulation of neddylation is known to be strongly associated with cancer.
  • Object of the present invention is therefore a pyrrole compound of formula (I) for anticancer use through the inhibition of the protein Glycyl-tRNA Synthase 1 (GARS1) or for the modulation of the activity of the protein Glycyl-tRNA Synthase 1 (GARS1).
  • the use of the pyrrole compound of formula (I) as an inhibitor of the protein Glycyl-tRNA Synthase 1 determines the inhibition of the neddylation pathway and the studies undertaken have demonstrated a powerful antiproliferative effect on the A549 and H460 cells resistant to Platinum compounds (PTX).
  • PTX Platinum compounds
  • GARS1 was indicated as an important player in the biological effect induced by the compound of formula (I) as observed in A549 cells.
  • PBS turned out to be partially overlapping the region occupied by the natural substrates glycine and ATP (which in this specific structure was replaced by AMPPNP (i.e. ANP) to improve the quality of the diffraction data). It was therefore possible to find an inhibition of the catalytic activity of GARS1 by the compound of formula (I) or of formula (II) as a possible cause of the effects observed experimentally induced by the same compound.
  • AMPPNP i.e. ANP
  • the invention relates to a pyrrole compound of formula (I):
  • R is a linear or branched C1-C4 alkyl, 3-aminophenyl, 4-aminophenyl, 3-N- phenylacetamide, 4-N-phenylacetamide, 3-N-phenylpropanamide or 4-N-phenylpropanamide, for use as an inhibitor of protein Glycyl-tRNA Synthase 1 (GARS1) or for the modulation of the activity of the protein Glycyl-tRNA Synthase 1 (GARS1).
  • pyrrole compound is meant the compound described above, having four pyrrole rings, wherein each pyrrole ring is a five membered heterocycle, one of which is a nitrogen atom.
  • linear or branched C1-C4 alkyl is meant methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl.
  • An inhibitor is a substance that interferes with the activity of an enzyme and slows down the rate of the reaction it catalyses.
  • the pyrrole compound of formula (I), previously described, is used as an inhibitor of the protein Glycyl-tRNA Synthase 1 (GARS1).
  • GAS1 Glycyl-tRNA Synthase 1
  • treatment methods we mean a procedure or process or action of any kind and nature (physical, chemical, material, etc.) to which a material or a product, a substance, an organism or part thereof is subjected, in order to achieve certain effects.
  • R of the pyrrole compound of formula (I) or of formula (II) is methyl, 4-aminophenyl, 3-N-phenylacetamide or 4- N-phenylacetamide.
  • R of the pyrrole compound of formula (I) is methyl or 3-N-phenylacetamide.
  • the pyrrole compound of formula is used as an inhibitor of the enzymatic activity of the protein Glycyl-tRNA Synthase 1 (GARS1) or is used in methods of treating the enzymatic activity of the protein Glycyl-tRNA Synthase 1 (GARS1).
  • the pyrrole compound of formula (I) is used in treatment methods aimed at inhibiting the enzymatic activity of the protein Glycyl-tRNA Synthase 1 (GARS1).
  • Enzyme activity is the rate at which a reaction proceeds towards equilibrium in the presence of an enzyme. Knowing that biological reactions are characterized by a high activation energy and can only take place thanks to the enzymes that act as biological catalysts. They are mainly made up of proteins and have the function of increasing the speed of a reaction by acting only on the kinetic aspect of the same as they lower its activation energy.
  • Enzymes are endowed with high specificity, i.e. they catalyze only a certain reaction according to the key-lock model, according to which the enzyme and the substrate have an exactly complementary shape which allows them to fit perfectly together.
  • Enzymes also have an active site that binds to the substrate(s). Therefore, in general, for enzymatic catalysis to occur it is necessary for the enzyme and the substrate to collide according to a certain orientation and form a complex, namely an adduct which then evolves in the reaction.
  • the enzymatic activity through various factors can be accelerated, slowed down or even inhibited. These factors can be: temperature, pH, concentration, concentration of the substrate, enzyme or products, but also the presence of activators and inhibitors.
  • inhibitors are substances that decrease enzyme activity or render the enzyme inactive.
  • Inhibitors are generally small molecules which, by binding to the enzyme, reduce its activity by modifying the affinity towards the substrate, as described previously and in detail.
  • the pyrrole compound of formula (I) is specifically used in treatment methods aimed at inhibiting the enzymatic activity of the protein Glycyl-tRNA Synthase 1 (GARS1), thus inactivating the aforementioned protein.
  • the pyrrole compound of formula (I) is used when the nedylation activity supported by the protein Glycyl-tRNA Synthase 1 (GARS1) is overexpressed in tumor diseases, as is the case of "non-small cell” lung cancer (NSCLC).
  • the pyrrole compound of formula (I) is used to inhibit the enzymatic activity of the protein Glycyl-tRNA Synthase 1 (GARS1) which is found to be over-impressed and hyperactive in its ability to effect nedylation in some diseases cancerous.
  • GAS1 Glycyl-tRNA Synthase 1
  • Tumor disease is a pathological condition characterized by the uncontrolled proliferation of cells that have the ability to infiltrate the normal organs and tissues of the body, altering their structure and functioning.
  • Glycyl-tRNA Synthase 1 (GARS1)
  • Glycyl-tRNA Synthase 1 (GARS1)
  • the pyrrole compound of formula (I) is used when the activity supporting the exerted nedylation of the protein Glycyl- tRNA Synthase 1 (GARS1) is overexpressed in "non-small cell” lung cancer (NSCLC).
  • Glycyl- tRNA Synthase 1 Glycyl- tRNA Synthase 1
  • Non-small cell lung cancer is a type of malignant lung cancer that differs from smallcell lung cancer (SCLC) by the appearance of the tumor cells under a microscope (also for the biological characteristics of the tumor).
  • SCLC smallcell lung cancer
  • NSCLC is divided into other subtypes, with the three main types being adenocarcinoma, squamous cell carcinoma, and large cell (undifferentiated) carcinoma of the lung.
  • NSCLC Lung cancer is the third most common malignancy in Europe; NSCLC accounts for 85- 90% of all lung malignancies. It was also found that as a class, NSCLCs are relatively insensitive to chemotherapy.
  • the pyrrole compound of formula (I) is then used to inhibit the activity of the protein Glycyl-tRNA Synthase 1 (GARS1) which is overexpressed in "non-small cell” lung cancer (NSCLC), favoring the nedylation process (REF_CAM_1 ).
  • GAS1 Glycyl-tRNA Synthase 1
  • NSCLC non-small cell lung cancer
  • the pyrrole compound of formula (I) is used when the enzymatic activity of the protein Glycyl-tRNA Synthase 1 (GARS1) is expressed in non-small cell lung cancer (NSCLC) of the lung cancer lineage (A549).
  • Glycyl-tRNA Synthase 1 Glycyl-tRNA Synthase 1
  • a cell line is a clonal, genetically stable population of normal or neoplastic cells capable of proliferating in vitro. While cells of neoplastic origin are able to proliferate indefinitely, normal cells undergo a phenomenon of clonal senescence and after a defined number of cell divisions (about 40) they lose the ability to divide.
  • the A549 cell line identifies a lung adenocarcinoma.
  • the pyrrole compound of formula (I) is used in a concentration ranging from 5 to 20 pM, or in a concentration of about 10 pM.
  • the pyrrole compound of formula (I) is used in a concentration of about 10 pM.
  • the pyrrole compound of formula (I) is used in the inhibition of the enzymatic activity of the protein Glycyl-tRNA Synthase 1 (GARS1) or is used in methods of treating the enzymatic activity of the protein Glycyl-tRNA Synthase 1 (GARS1), wherein said enzymatic activity occurs in-vitro, in-vivo and ex-vivo.
  • the invention also relates to the use of the above-described pyrrole compound as an anti-tumor agent.
  • SPILLO-PBSS SPILLO Potential Binding Sites Searcher
  • SPILLO-PBSS Percentive Binding Sites Searcher
  • this SPILLO-PBSS takes into account the flexibility of proteins and recognizes target and non-target (off-target) proteins of any small molecule even when the protein binding sites are strongly distorted (e.g., too open, busy, or even completely closed closed), with respect to a conformation suitable for binding.
  • SPILLO-PBSS has recently been used in projects - where target and off-target proteins of other small molecules have been successfully identified at the proteomic scale and experimentally validated.
  • the protein database used for SPILLO-PBSS screening was generated by collating all available apo- and holo-3D protein structures in the RCSB PDB protein database [REF_SP_1] (updated June 2020) for Homo sapiens organisms (45,872 3D structures), Mus musculus (6,474 3D structures entries), and Rattus norvegicus (2,970 3D structures) experimentally resolved by X-ray diffraction or solution NMR, including sequence redundancies, for a total of 55,316 3D structures.
  • the multimeric biological assemblies were generated by the MakeMultimer program [REF_SP_1 b] according to the BIOMT transformation matrices included in the PDB files. For multi-model PDB files from solution NMR experiments, only the first model was included in the database. No further refinements were performed to improve the quality of the 3D protein structures in the database.
  • the reference binding site (Reference Binding Site: RBS) used by SPILLO-PBSS to identify potential targets of the aforementioned compound was obtained using molecular action modeling techniques and the standard RBS generation protocol described in the reference document PIN-PBSS. It comprised 22 amino acids directly interacting with the aforementioned compound, without any water-mediated contact.
  • SPILLO-PBSS By means of SPILLO-PBSS a systematic and error-free (unbiased) search of the potential binding sites (PBS) of the aforementioned compound was carried out within all the 3D protein structures included in the database.
  • SPILLO-PBSS analyzed all the proteins in the database and a PBS ranking was obtained by the molecule for each protein.
  • the proteins in the database were then sorted (descending order) according to the score of the highest PBS, which represents the highest similarity to the corresponding RBS, obtained from each 3D structure of the analyzed protein.
  • the SPILLO-PBSS software was used to select and classify a large Protein database including available structural proteomes (55,316 3D protein structures, June 2020) of three different organisms, namely Homo sapiens, Mus musculus and Rattus norvegicus. This analysis led to the graph shown in Figure 1 , where the dots correspond to proteins ranked in descending order according to the greatest similarity between the RBS and the best PBS identified within each 3D structure of the protein.
  • GARS (5pM) is incubated in a reaction buffer containing 50 mM HEPES, pH 7.5, 20 mM KCI, 5 mM MgCI2, 1 mM DTT, 5 mM ATP at 25°C.
  • AP4A diadenosine tetraphosphate
  • the quenched solutions are incubated for 10 min with 200 pl of 3 mM ammonium molybdate in 0.6 M HCI (60% CH3CN/W).
  • the colorimetric reaction is started by adding 80 pL of a solution of ascorbic acid (500 mM) in 2M HCI (60% CH3CN/W). After 10 minutes the optical absorbance at 790 nm is measured.
  • Calibration curves for determining pyrophosphate concentration are routinely obtained using standard solutions containing pyrophosphate in the range 0-50 pM.
  • Example 3 Effects of the enzymatic activity of GARS from the use of the compound of formula (I) of the present invention:
  • GARS (0.5pM) was incubated in a reaction buffer containing 5mM HEPES, pH 7.5, 2mM KCI, 0.5mM MgCI2, 100uM DTT, 5mM ATP at 25°C.
  • AP4A diadenosine tetraphosphate
  • the solutions were prepared in DMSO such that the concentration of DMSO per well did not exceed 1% and that the volumes added to each well were the same.
  • a first dose of 5 mg/kg was injected subcutaneously, which was increased 5-fold to a final dose of 50-fold (250 mg/kg).
  • FRAISINIB is a potential therapeutic agent against NSCLC tumors in experimental animal models.
  • the tumor volume of the group treated with FRAISINIB was reduced by 89.24% while the weight of the tumor was reduced by 68.93%.

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Abstract

L'invention concerne un composé pyrrole de formule (I) : 5 (I) dans laquelle R est un alkyle en C1-C4 linéaire ou ramifié, un 3-aminophényle, un 4-aminophényle, un 3-N-phénylacétamide, un 4-N-phénylacétamide, un 3-N-phénylpropanamide ou un 4-N-phénylpropanamide, destinés à être utilisés en tant qu'inhibiteurs de la protéine glycyl-ARNt synthase 1 (GARS1) ou 10 à être utilisés dans des méthodes de traitement à la protéine glycyl-ARNt synthase 1 (GARS1).
PCT/IB2023/054699 2022-05-09 2023-05-05 Activité antitumorale de méso-(p-acétamidophényl)-calix[4]pyrrole par inhibition de l'activité enzymatique de la protéine glycyl-arnt synthase 1 (gars1) WO2023218306A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020115566A1 (en) * 1996-04-05 2002-08-22 Sessler Jonathan L. Halogenated calixpyrroles, calixpyridinopyrroles and calixpyridines, and uses thereof
WO2018061045A1 (fr) * 2016-09-29 2018-04-05 UNIVERSITA' DEGLI STUDI Dl MESSINA Composés antitumoraux à base de calixpyrrole
US20190381086A1 (en) * 2015-10-14 2019-12-19 The Scripps Research Institute INHIBITION OF NEDDYLATION USING GLYCYL-tRNA SYNTHETASE INHIBITORS
WO2020047268A1 (fr) * 2018-08-29 2020-03-05 Research Institute At Nationwide Children's Hospital Compositions et procédés pour l'inhibition de l'expression de la protéine gars mutante

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020115566A1 (en) * 1996-04-05 2002-08-22 Sessler Jonathan L. Halogenated calixpyrroles, calixpyridinopyrroles and calixpyridines, and uses thereof
US20190381086A1 (en) * 2015-10-14 2019-12-19 The Scripps Research Institute INHIBITION OF NEDDYLATION USING GLYCYL-tRNA SYNTHETASE INHIBITORS
WO2018061045A1 (fr) * 2016-09-29 2018-04-05 UNIVERSITA' DEGLI STUDI Dl MESSINA Composés antitumoraux à base de calixpyrrole
WO2020047268A1 (fr) * 2018-08-29 2020-03-05 Research Institute At Nationwide Children's Hospital Compositions et procédés pour l'inhibition de l'expression de la protéine gars mutante

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"UniProtKB", Database accession no. P41250

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