WO2012038918A1 - Produit thérapeutique inhibiteur de la prolifération cellulaire et applications biologiques associées - Google Patents

Produit thérapeutique inhibiteur de la prolifération cellulaire et applications biologiques associées Download PDF

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Publication number
WO2012038918A1
WO2012038918A1 PCT/IB2011/054168 IB2011054168W WO2012038918A1 WO 2012038918 A1 WO2012038918 A1 WO 2012038918A1 IB 2011054168 W IB2011054168 W IB 2011054168W WO 2012038918 A1 WO2012038918 A1 WO 2012038918A1
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WIPO (PCT)
Prior art keywords
arppl9
gwl
mitotic
pp2a
endosulfme
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PCT/IB2011/054168
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English (en)
Inventor
Anna Castro
Aïcha GHARBI
Thierry Lorca
Jean-Claude Labbe
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Centre National De La Recherche Scientifique (Cnrs)
Universite Montpellier 2
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Publication of WO2012038918A1 publication Critical patent/WO2012038918A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/20—Fusion polypeptide containing a tag with affinity for a non-protein ligand
    • C07K2319/23—Fusion polypeptide containing a tag with affinity for a non-protein ligand containing a GST-tag

Definitions

  • the invention relates to specific inhibitors of the cell cycle deregulation and the biological applications thereof.
  • Mitotic entry and exit were historically thought to be directly dependent on the activation and inactivation of the cyclin B-Cdc2 complex. Recent results have expanded this model to include phosphatases. New data indicates that maintenance of phosphorylations on mitotic proteins is not exclusively dependent on cyclin B- Cdc2 kinase, but also on the activity of the phosphatase PP2A, which is the main phosphatase responsible for the dephosphorylation of mitotic substrates although a role of PP1 has also been reported in Xenopus egg extracts. Therefore the balance between cyclin B-Cdc2 and PP2A activities determines the timing of mitotic entry and exit.
  • PP2A regulation might then be mediated by phosphorylation, however, while Gwl and PP2A can interact, a direct phosphorylation on PP2A by this kinase, has never been observed suggesting that Gwl inhibits PP2A through an intermediary protein.
  • the inventors used biochemical fractionation of Xenopus egg extracts and in vitro phosphorylation with a hyperactive form of human Gwl to identify the first substrates of this kinase.
  • Interphase Xenopus egg extracts were first fractionated with a heparin column. The elution of this column was subsequently submitted to ammonium sulphate precipitation (cut off 50-70%) and finally resuspended and fractionated by Gel Filtration. The different fractions were subsequently phosphorylated in vitro with a hyperactive form of human Gwl (K72M mutant) (7) and the phosphorylated bands were analysed by mass spectrometry. Maximal phosphorylation was observed in the Gel Filtration fractions corresponding to molecular weights of 30 to 70 ( Figure 1A, Fraction 3) and 20 to 50 kDa ( Figure 1A, Fraction 4).
  • oocytes from Drosophila with mutant a-Endosulfine have a prolonged prophase and fail to progress to metaphase.
  • these oocytes contain normal mitotic levels of in vitro Cdc2 kinase activity, but importantly show a reduced amount of in vivo phosphorylation on mitotic substrates, a phenotype pronounced to the one observed in Gwl-depleted Xenopus egg extracts.
  • cyclin B-Cdc2 and PP2A Two different activities, cyclin B-Cdc2 and PP2A, must be regulated to promote mitotic entry. It is known that Gwl mediates entry into mitosis through the inhibition of PP2A, and thus, phosphorylated Arppl9 and ⁇ -Endosulfme probably mediate mitotic entry by directly inhibiting PP2A. However, the possibility that these two proteins could also regulate cyclin B-Cdc2 activity to promote entry into mitosis cannot be excluded.
  • Arppl9 and ⁇ -Endosulfme are the downstream substrates of Gwl that promote mitotic entry, likely through the regulation of PP2A, but not through the regulation of cyclin B-Cdc2.
  • Arppl9 is the main substrate of Gwl responsible of PP2A inhibition at mitotic entry.
  • Phosphorylations occur through cyclin B-CDC2 kinase and result in mitose activation.
  • a specific subpopulation of PP2A phosphatases is involved in the dephosphorylations, i.e. PP2A-B555 isoform. It results in mitose inhibition.
  • the invention thus relates to Arppl9 and/or ⁇ -Endosulfme for use as specific inhibitors of the cell deregulation.
  • It also relates to a therapeutic product inhibitor of cell proliferation through PP2A, more particularly PP2A-B555 pathway.
  • the invention more particularly relates to the use as inhibitors of PP2A ⁇ 55 ⁇ complex of Arppl9 and CC-Endosulfme. Said compounds are valuable tools for therapy and in vitro diagnostic of pathologies resulting from cell cycle deregulation such as cancer.
  • compositions comprising an efficient amount of Arppl9 and cc- Endosulfine in association with pharmaceutically acceptable carriers are also covered by the invention.
  • active ingredients used in therapeutically effective amounts are mixed with the pharmaceutically acceptable vehicles for the mode of administration chosen.
  • These vehicles may be solids or liquids or gels.
  • the amount of active principle in the drugs will be easily determined by those skilled in the art in view of the pathology to be treated.
  • the doses per dosage unit will be chosen depending on the condition and age of the patient.
  • the invention also encompasses an in vitro diagnostic method of pathologies original due to a cell cycle deregulation such as cancer comprising the use of Arppl9 and cc- Endosulfine. It also relates to a method of inhibiting said complex using Arppl9 and cc- Endosulfine.
  • Figure 1 Addition of Arp l9 and cc-Endosulfine previously phosphorylated in vitro by Gwl to interphase extracts promotes mitotic entry.
  • A Coomassie Blue staining and autoradiography of two fractions of gel filtration in which a band of 20 kDa was highly phosphorylated in vitro. Arrowheads show bands that were analysed by mass spectrometry.
  • B In vitro phosphorylation of Gst-Arppl9 and Gst-cc- Endosulfine by Gwl.
  • Interphase extracts were depleted of Cdc27 and supplemented at a final concentration of 170 ng/ ⁇ with the proteins Gst-Arppl9 and Gst-a-Endosulfme phosphorylated or not in vitro by Gwl.
  • the Gwl-phosphorylation mutants Arppl9- S62A and a-Endosulfine-S67A were also submittd to in vitro phosphorylation and supplemented to these extracts.
  • Mitotic entry was analysed in interphase extracts that were depleted of Cdc27 and Cdc25 and supplemented with phospho-Arppl9 and phospho-a-Endosulfme (final concentration 170 ng/ ⁇ ).
  • C Interphase extracts were depleted of Cdc27 and Gwl and subsequently supplemented with phosphorylated or thiophosphorylated Arppl9 and a-Endosulfine.
  • D Mitotic extracts (CSF) were supplemented with thiophosphorylated Arppl9 or a-Endosulfine and subsequently depleted of Gwl.
  • FIG. 3 Phosphorylated Arppl9 and ⁇ -Endosulfine bind and inhibit PP2A.
  • A Interphase or mitotic extracts were supplemented with Gst-Sepharose, Gst-Arppl9- Sepharose, Gst-a-Endosulfme-Sepharose, the Gst-Arppl9 (S62A)-Sepharose or Gst- a-Endosulfme (S67A)-Sepharose and twenty minutes later the binding of PP2A subunits A and C were analysed by GST pull down and western blot.
  • FIG. 4 Endogenous Arppl9 but not ⁇ -Endosulfine is required to promote correct entry into mitosis.
  • A Interphase extracts were depleted of Cdc27 and either Arppl9 or a-Endosulfine and subsequently supplemented with cyclin A (final concentration 60 nM).
  • B Mitotic extracts were depleted of Arppl9 or a- Endosulfme and the mitotic state was analysed.
  • C 20 ⁇ of interphase and mitotic egg extracts were immunoprecipitated with anti-C terminal a-Endosulfine or anti- human Arppl9 and the phosphorylation of these two proteins on the Gwl specific site was analysed.
  • the staining signal was measured and quantified by using ImageJ software
  • D Mitotic extracts were depleted of Cdc27 and Arppl9 and 20 minutes later were (+OA) or not (-OA) supplemented with Okadaic Acid (final concentration 0.7 ⁇ ) and the mitotic state was analysed.
  • E HeLa cells were transfected or not (Lipo), with scramble (SC) or 50 or 100 nM of Arppl9 siRNA for 24 h, then synchronized by thymidine and released into nocodazole (50 ng/ml) for 10 h. The percentage of mitotic cells was measured by a 2D-FACS (propidium iodide/anti- phospho Serine Cdk antibody).
  • the percentage of mitotic cells at each condition was expressed as mean ⁇ S.D. Statistical differences between scramble versus either 50 nM or 100 nM Arppl9 siRNA are indicated. (*p ⁇ 8.03E-06 and * p ⁇ ! 45E--0 ). The cellular levels of endogenous Arppl9 at each condition are shown.
  • Polyclonal phospho-tyrosine 15 Cdc2, anti-phospho-(Ser) CDK substrate and monoclonal PP2A/A (6G3) antibodies were obtained from Cell Signalling Technology Inc. Affinity purified antibodies against Gwl, Cdc27, cyclin A, cyclin B2 and Cdc25, were obtained as previously described (3-8). Monoclonal antibody anti-PP2A C subunit (1D6) was obtained from Upstate/Millipore. Phospho-S67/S62 Endo/Arpp antibody was obtained from Dr T. Hunt and Dr S Mochida.
  • Human pBKS-Arppl9 and pBKS-a-Endosulfme were subcloned into the EcoRl-Notl site of pGEX4T and into the EcoRl-Xhol site of pMal.
  • the fusion proteins were expressed in Escherichia coli and the soluble fraction was purified using glutathione-sepharose and MBP-sepharose beads.
  • Gst-human Arppl9 soluble protein was used to immunize rabbits. Immune sera was affinity purified on immobilized MBP-human Arppl9 column.
  • C-terminal-Xenopus ⁇ -Endosulfme antibodies were generated against the last 1 1 aminoacids of the C-terminal sequence of this protein.
  • Peptides were coupled to thyroglobulin for immunization and to immobilized bovine serum albumin for affinity purification.
  • Mitotic egg extracts were prepared from unfertilized Xenopus eggs that were arrested at metaphase of the second meiotic division as previously described (9). Interphase egg extracts were prepared from de-jellied unfertilized eggs transferred in MMR/4 (25 mM NaCl, 0.5 mM KC1, 0.25 nM MgCl 2 , 0.025 mM Na EGTA, 1.25 mM HEPES-NaOH ph 7.7) Extracts were prepared 40 minutes after ionophore addition by the same procedure as described for mitotic extracts.
  • Extract (1 ⁇ ) was frozen in liquid nitrogen at the indicated times. Samples were then thawed by the addition of l9 ⁇ of HI buffer including [ ⁇ 33 ⁇ ] ⁇ and incubated for lO min at room temperature (10). Reactions were stopped by adding Laemmli sample buffer and analysed by SDS-PAGE.
  • Radiolabeled p-mal-cMos was then added to each immunoprecipitated and incubated for the indicated times at 30°C in dephosphorylation buffer (50 mM Tris pH 8, 100 ⁇ CaCl 2 ).
  • dephosphorylation buffer 50 mM Tris pH 8, 100 ⁇ CaCl 2 .
  • hyperactive Gwl was immunoprecipitated from 20 ⁇ CSF translated extracts.
  • the IP was subsequently washed three times with RIPA (NaH 2 P0 4 lOmM, NaCl lOOmM, EDTA 5mM, Triton XI 00 1%, deoxycholate 0.5 %, ⁇ -glycerophosphate 80 ⁇ , NaF 50 mM, DTT 1 mM), twice with Tris 50 mM ph 7.5 and subsequently used to phosphorylate 12.5 ⁇ g of each of these proteins of sample buffer containing ATP-5S (HEPES 20 mM, Mg Cl 2 10 mM, ATP-5S 1 mM) at a final volume of 7 ⁇ .
  • RIPA NaH 2 P0 4 lOmM, NaCl lOOmM, EDTA 5mM, Triton XI 00 1%, deoxycholate 0.5 %, ⁇ -glycerophosphate 80 ⁇ , NaF 50 mM, DTT 1 mM
  • RNAiMax Reagent Initrogen
  • cells were transfected with the corresponding siRNA for 24 hours and subsequently synchronized with thymidine (2.5 mM) a subsequent period of 24 hours.
  • thymidine 2.5 mM
  • cells were released into 50 ng/ml of Nododazole and analysed by 2D-FACS (propiddium iodide and anti-phospho-(Ser) Cdk substrate antibody) to determinate the percentage of mitotic cells.
  • 2D-FACS propiddium iodide and anti-phospho-(Ser) Cdk substrate antibody

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Abstract

Selon l'invention, Arpp19 et/ou α-Endosulfine peuvent être utilisés en tant qu'inhibiteurs spécifiques de la dérégulation du cycle cellulaire. L'invention concerne également des applications biologiques associées.
PCT/IB2011/054168 2010-09-23 2011-09-22 Produit thérapeutique inhibiteur de la prolifération cellulaire et applications biologiques associées WO2012038918A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014201021A2 (fr) * 2013-06-10 2014-12-18 Dana-Farber Cancer Institute, Inc. Procédés et compositions pour réduire l'immunodépression par des cellules tumorales
CN105561336A (zh) * 2014-10-17 2016-05-11 上海中医药大学附属龙华医院 Arpp-19基因在制备治疗肝癌的药物中的用途

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US20020137203A1 (en) * 2000-12-13 2002-09-26 Wiles Michael V. Transgenic mice containing alpha-endosulfine gene disruptions

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US20020137203A1 (en) * 2000-12-13 2002-09-26 Wiles Michael V. Transgenic mice containing alpha-endosulfine gene disruptions

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014201021A2 (fr) * 2013-06-10 2014-12-18 Dana-Farber Cancer Institute, Inc. Procédés et compositions pour réduire l'immunodépression par des cellules tumorales
WO2014201021A3 (fr) * 2013-06-10 2015-02-26 Dana-Farber Cancer Institute, Inc. Procédés et compositions pour réduire l'immunodépression par des cellules tumorales
CN105431524A (zh) * 2013-06-10 2016-03-23 达娜-法勃肿瘤研究所公司 用于降低通过肿瘤细胞的免疫抑制的方法和组合物
JP2016526883A (ja) * 2013-06-10 2016-09-08 デイナ ファーバー キャンサー インスティチュート，インコーポレイテッド 腫瘍細胞による免疫抑制を低下させるための方法および組成物
US9944931B2 (en) 2013-06-10 2018-04-17 Dana-Farber Cancer Institute, Inc. Methods and compositions for reducing immunosupression by tumor cells
EA035475B1 (ru) * 2013-06-10 2020-06-23 Дана-Фарбер Кэнсер Инститьют, Инк. Способы и композиции для снижения иммуносупрессии опухолевыми клетками
US10876120B2 (en) 2013-06-10 2020-12-29 Dana-Farber Cancer Institute, Inc Methods and compositions for reducing immunosupression by tumor cells
EP3892293A1 (fr) * 2013-06-10 2021-10-13 Dana-Farber Cancer Institute, Inc. Procédés et compositions pour réduire l'immunosuppression par des cellules tumorales
US11597934B2 (en) 2013-06-10 2023-03-07 Dana Farber Cancer Institute, Inc. Methods and compositions for reducing immunosuppression by tumor cells
CN105561336A (zh) * 2014-10-17 2016-05-11 上海中医药大学附属龙华医院 Arpp-19基因在制备治疗肝癌的药物中的用途
CN105561336B (zh) * 2014-10-17 2019-09-20 上海中医药大学附属龙华医院 Arpp-19基因在制备治疗肝细胞性肝癌的药物中的用途

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