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WO1997018323A2 - Materiaux de kinase relatifs a la phosphatidylinositol kinase du point de controle du cycle cellulaire, et procedes - Google Patents

Materiaux de kinase relatifs a la phosphatidylinositol kinase du point de controle du cycle cellulaire, et procedes Download PDF

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Publication number
WO1997018323A2
WO1997018323A2 PCT/US1996/019337 US9619337W WO9718323A2 WO 1997018323 A2 WO1997018323 A2 WO 1997018323A2 US 9619337 W US9619337 W US 9619337W WO 9718323 A2 WO9718323 A2 WO 9718323A2
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Prior art keywords
dna
mccs1
kinase
cell
seq
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PCT/US1996/019337
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WO1997018323A3 (fr
Inventor
Merl F. Hoekstra
Doug A. Holtzman
Kathleen S. Keegan
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Icos Corp
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Icos Corp
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Priority to SK1115-97A priority Critical patent/SK111597A3/sk
Application filed by Icos Corp filed Critical Icos Corp
Priority to IL12130696A priority patent/IL121306A0/xx
Priority to FI973005A priority patent/FI973005A7/fi
Priority to EP96945181A priority patent/EP0807169A3/fr
Priority to JP51918097A priority patent/JP2002515732A/ja
Priority to HU0002207A priority patent/HUP0002207A2/hu
Priority to MX9705466A priority patent/MX9705466A/es
Priority to AU14611/97A priority patent/AU1461197A/en
Publication of WO1997018323A2 publication Critical patent/WO1997018323A2/fr
Priority to NO973279A priority patent/NO973279L/no
Publication of WO1997018323A3 publication Critical patent/WO1997018323A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/10—Transferases (2.)
    • C12N9/12—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
    • C12N9/1205—Phosphotransferases with an alcohol group as acceptor (2.7.1), e.g. protein kinases

Definitions

  • the checkpoint kinases play a role in the surveillance of DNA damage that occurs as a result of replication errors, DNA mismatches, radiation treatment, or chemotherapeutic drugs. These kinases are required in regulatory pathways that lead to cell cycle arrest following DNA damage, giving the cell notice and time to correct lesions prior to the initiation of DNA replication. More particularly, the invention relates to a novel human PIK-related kinase, Mammalian Cell Cycle Surveillance 1 (MCCS1), polynucleotides encoding the PIK-related kinase, and methods for assaying and modulating the enzymatic activity of the kinase and related kinases.
  • MCCS1 Mammalian Cell Cycle Surveillance 1
  • the process of eukaryotic cell growth and division is the somatic or mitotic cell cycle which consists of four phases, the G 1 phase, the S phase, the G 2 phase, and the M phase.
  • the G 1 , S, and G 2 phases are collectively referred to as interphase of the cell cycle.
  • the cell cycle is structurally and functionally conserved in its basic process and mode of regulation across all eukaryotic species.
  • G 1 (gap) phase biosynthetic activities of the cell progress at a high rate.
  • the S (synthesis) phase begins when DNA synthesis starts and ends when the DNA content of the nucleus of the cell has been replicated and two identical sets of chromosomes are formed.
  • AT human disease syndrome ataxiatelangiectasia
  • Ataxia-Telangiectasia Mutated (ATM) gene was recently described in Savitsky et al., Science, 268: 1749-1753 (1995) and the partial cDNA encodes a protein with amino acid similarity to the rad3+ gene.
  • Savitsky et al., Human Molecular Genetics, 4(11);2025-2032 (1995) describes isolation of a cDNA encoding full length ATM.
  • the increased radiosensitivity of rad3+ yeast mutants and of mammalian cells lacking functional ATM suggests that these proteins may comprise a family of checkpoint proteins.
  • Substrates of MCCS1 and proteins which interact with MCCS1 may be identified by various assays.
  • a polynucleotide encoding a protein that interacts with MCCS1 is isolated by: transforming or transfecting appropriate host cells with a DNA construct comprising a reporter gene under the control of a promoter regulated by a transcription factor having a DNA binding domain and an activating domain; expressing in the host cells a first hybrid DNA sequence encoding a first fusion of part or all of MCCS1 and either the DNA binding domain or the activating domain of the transcription factor; expressing in the host cells a library of second hybrid DNA sequences encoding second fusions of part or all ofputative MCCS1 binding proteins and the DNA binding domain or activating domain of the transcription factor which is not incorporated in the first fusion; detecting binding ofan MCCS1 interacting protein to MCCS1 in a particular host cell by detecting the production of reporter gene product in the host cell; and isolating second hybrid DNA sequences encoding the interacting protein from the particular host cell.
  • Presently preferred for use in the assay are a lex
  • the invention contemplates that mutations in the MCCS1 gene that result in loss of normal function of the MCCS1 gene product underlie human disease states in which failure of the G 2 cell cycle checkpoint is involved. Gene therapy to restore MCCS1 activity would thus be indicated in treating those disease states (for example, testicular cancer). Delivery of a functional MCCS1 gene to appropriate cells is effected in vivo or ex vivo by use of viral vectors (e.g., adenovirus, adeno-associated virus, or a retrovirus) or ex vivo by use ofphysical DNA transfer methods (e.g. , liposomes or chemical treatments).
  • viral vectors e.g., adenovirus, adeno-associated virus, or a retrovirus
  • physical DNA transfer methods e.g. , liposomes or chemical treatments.
  • an assay for identifying modulators of MCCS1 kinase activity involves incubating an MCCS1 kinase preparation in kinase buffer with gamma- 32 P-ATP and an exogenous kinase substrate, both in the presence and absence of a test compound, and measuring the moles of phosphate transferred to the substrate. An increase in the moles of phosphate transferred to the substrate in presence ofthe test compound compared to the moles ofphosphate transferred to the substrate in the absence of the test compound indicates that the test compound is an activator of said MCCS1 kinase.
  • assays for identifying compounds that modulate interaction ofMCCS1 with other proteins may involve: transforming or transfecting appropriate host cells with a DNA construct comprising a reporter gene under the control of a promoter regulated by a transcription factor having a DNA-binding domain and an activating domain; expressing in the host cells a first hybrid DNA sequence encoding a first fusion of part or all of MCCS1 and the DNA binding domain or the activating domain of the transcription factor; expressing in the host cells a second hybrid DNA sequence encoding part or all of a protein that interacts with MCCS1 and the DNA binding domain or activating domain of the transcription factor which is not incorporated in the first fusion; evaluating the effect of a test compound on the interaction between MCCS1 and the interacting protein by detecting binding of the interacting protein to MCCS1 in a particular host cell by measuring the production of reporter gene product in the host cell in the presence or absence of the test compound; and identifying modulating compounds as those test compounds altering production of the reported gene product in comparison
  • a composite cDNA encoding MCCS1 ⁇ was constructed from clones HFB2, HT9 and HT2.
  • the three clones werejoined together by digesting HFB2 with the restriction enzymes Kpnl and Sail to generate a fragment to comprise the 5' end of the composite clone, digesting HT9 with Kpnl and NotI to generate a fragment to comprise the 3' end of the composite clone, and then ligating isolated fragments to the vector pBS SK- (Stratagene) that had been digested with Sail and NotI.
  • the region of the HT9 fragment containing the one nucleotide insertion was replaced with an EcoRV fragment containing nucleotides 3174 to 5282 of clone HT2.
  • the final plasmid containing a 7621 bp insert was named pBSHFB2HT2-27 (ATCC 69951).
  • the DNA and deduced amino acid sequence of the insert are presented in SEQ ID NOs: 1 and 2, respectively.
  • the coding domain of the cDNA initiates with an ATG at nucleotide 333 and ends with a termination codon at nucleotide 7560 predicting a coding sequence of 2409 amino acids and protein of 265 kD.
  • the protein product of the cDNA insert was named MCCS1 ⁇ .
  • Subsequent sequence analysis of the insert in plasmid pBSHFB2HT2-27 revealed sequencing errors in SEQ ID NO: 1.
  • a composite clone containing the complete coding sequence of MCCS1 ⁇ (with the seventy amino acid insert) is presented in SEQ ID NO: 32.
  • the amino acid sequence deduced from the clone is presented in SEQ ID NO: 33.
  • This clone is constructed by replacing the sequence between the BSTXI site, which cleaves after nucleotide 3229, and the NotI site in the polylinker sequence at the 3' end of pBSHFB2HT2-27 (SEQ ID NO: 1) with the sequence contained in HT2 between the BstXI site and the NotI site at the 3' end ofHT2.
  • Percent identity of nucleotides is shown in the top line, percent identity of amino acids is shown in the middle line, and percent similarity of amino acids (i.e., including identical amino acids and conservative variations in amino acids) is shown in the bottom line for each kinase in Table 1.
  • Conservative variation as used herein denotes biologically similar residues. Examples ofconservative variations include the substitution of one hydrophobic residue such as isoleucine, valine, leucine or methionine for another, or the substitution of one polar residue for another, such as the substitution of arginine for lysine, glutamic for aspartic acids, or glutamine for asparagine, and the like.
  • ND indicates a value was not determined either because the nucleotide sequence encoding the kinase (i.e., rad3+) was not publically available or because the kinase (i.e., FRAP, p110 ⁇ , or PKA) lacks the particular domain being compared.
  • the samples were denatured for 4 minutes and then cycled 35 times with denaturing, annealing, and extension times of 45 seconds, 30 seconds, and 45 seconds, respectively, in a Model 480 Cetus Thermocycler. Five ⁇ l of the resulting PCR product was electrophoresed on a 3% agarose gel and stained with ethidium bromide.
  • DNA corresponding to the human/rodent chromosome 3 hybrid yielded a positive amplification product.
  • the coding region of MCCS1 is fused at the amino terminus to a heterologous peptide sequence, such as the FLAG tag MDYKDDDDK (SEQ ID NO:
  • MCCS1 associated protein kinase activity was immunoprecipitated using the MCCS1-specific polyclonal antibodies described in Example 5.
  • the expression pattern of MCCS1 in various human tissues was examined by Northern blot hybridization.
  • MCS1 mRNA and protein in normal and irradiated mouse testes and in mouse embryos was examined by in situ hybridization, immunostaining and/or immunoblotting.
  • the tissues were hybridized in situ with digoxigenin-labeled single-stranded mRNA generated from murine MCCS1 DNA by in vitro RNA transcription incorporating digoxigen-UTP (Boehringer Mannheim).
  • the labeled riboprobes see sequence in SEQ ID NO: 27
  • Testis tissue from normal male Balb/c mice was sectioned at 6 ⁇ m thickness, picked up on Superfrost Plus ® (VWR Scientific) slides and allowed to air-dry at room temperature overnight. Sections were stored at -70° C if not immediately used. The sections were fixed in cold (4°C) acetone for 10 minutes at room temperature; once the slides were removed from the acetone the reagent was allowed to evaporate from the sections. Each tissue section was blocked with 150 ⁇ l of a solution of 30% normal rat serum (Harlan Bioproducts), 5% normal goat serum (Vector Laboratories) and 1 % bovine serum albumin (BSA) (Sigma) in IX TBS for 30 minutes at room temperature.
  • BSA bovine serum albumin
  • Pachytene spermatocytes, round, and condensing spermatids were prepared from decapsulated testes of adult mice by sequential dissociation with collagenase and trypsin-DNase 1. The cells were separated into discrete populations by sedimentation velocity at unit gravity in 2-4% BSA gradients in Enriched Krebs
  • Substrates of MCCS1 and proteins that interact with MCCS1 may be identified by various assays.
  • Substrates of MCCS1 may be identified by incorporating test compounds in assays for kinase activity.
  • MCCS1 kinase is resuspended in 20 ⁇ l kinase buffer (25mM Hepes pH7.4, 25mM KCl, 10mM MgC12, ImM DTT, 2% glycerol, 0.1 % NP40, 0.5mM ATP, 10 uCI gamma 32 P-ATP) and incubated for 30 minutes, either in the presence or absence of 4 ⁇ g test compound (e.g., casein, histone H1 , or appropriate substrate peptide). Reactions are separated on 12% PAGE gels and dried onto Whatman paper prior to autoradiography. Moles of phosphate transferred by the kinase to the test compound are measured by autoradiography or scintillation counting. Transfer of phosphate indicates that the test compound is a substrate of the kinase.
  • PHAS-1 may be phosphorylated by several protein kinases in vivo including a protein kinase that is sensitive to rapamycin. Since the rapamycin-sensitive protein kinase, FRAP, is related to ATR, it would be reasonable to assume that there might be an overlap in substrate specificity between FRAP and ATR and that PHAS-1 is a substrate for both of these protein kinases in vitro.
  • FRAP rapamycin-sensitive protein kinase
  • ATR that was immunoprecipitated from a mouse testes cell extract orHis-tagged ATR purified from baculovirus-infected SF9 cells was incubated with 10 ⁇ g PHAS-1 (Stratagene) in kinase buffer (25 mM Hepes pH 7.4, 25 mM KCl, 10 mM MgCl 2 , 1 mM DTT, 0.1 % NP-40), 10 ⁇ M ATP and 10 ⁇ Ci 32 P ⁇ ATP for 20 minutes at 37oC.
  • Another type of assay for identifying MCCS1 interacting proteins involves immobilizing MCCS1 or a fragment thereof on a solid support coated (or impregnated with) a fluorescent agent, labelling a test protein with a compound capable ofexciting the fluorescent agent, contacting the immobilized MCCS1 with the labelled test protein, detecting light emission by the fluorescent agent, and identifying interacting proteins as test proteins which result in the emission of light by the florescent agent.
  • the putative interacting protein may be immobilized and MCCS1 may be labelled in the assay.
  • Modulators of MCCS1 include MCCS1 variants and other molecules.
  • the modulators may affect MCCS1 kinase activity, its localization in the cell, and/or its interaction with members of the cell cycle checkpoint pathway.
  • Presently preferred regions of MCCS1 which are targets for mutation or the development of selective modulators include the following four regions: the MCCS1 ⁇ amino terminal effector domain (amino acids 1 to 1081 of SEQ ID NO: 31), the MCCS1 ⁇ amino terminal effector domain (amino acids 1 to 1150 of SEQ ID NO: 33), the MCCS1 ⁇ rad3+ domain (amino acids 1082 to 2082 of SEQ ID NO: 31), the MCCS1 ⁇ rad3+ domain (amino acids 1151 to 2151 of SEQ ID NO: 33), the MCCS1 ⁇ PIK domain (amino acids 2083 to 2410 of SEQ ID NO: 31), and the MCCS1 ⁇ PIK domain (amino acids 2152 to 2480 of SEQ ID
  • assays for identifying compounds that modulate interaction ofMCCS1 with other proteins may involve: transforming or transferring appropriate host cells with a DNA construct comprising a reporter gene under the control of a promoter regulated by a transcription factor having a DNA-binding domain and an activating domain; expressing in the host cells a first hybrid DNA sequence encoding a first fusion of part or all ofMCCS1 and the DNA binding domain or the activating domain of the transcription factor; expressing in the host cells a second hybrid DNA sequence encoding part or all of a protein that interacts with MCCS1 and the DNA binding domain or activating domain of the transcription factor which is not incorporated in the first fusion; evaluating the effect of a test compound on the interaction between MCCS1 and the interacting protein by detecting binding of the interacting protein to MCCS1 in a particular host cell by measuring the production of reporter gene product in the host cell in the presence or absence of the test compound; and identifying modulating compounds as those test compounds altering production of the reported gene product in comparison to production
  • Yet another method contemplated by the invention for identifying compounds that modulate the binding between MCCS1 and an interacting protein involves immobilizing MCCS1 or a fragment thereof on a solid support coated (or impregnated with) a fluorescent agent, labelling the interacting protein with a compound capable of exciting the fluorescent agent, contacting the immobilized MCCS1 with the labelled interacting protein in the presence and absence of a test compound, detecting light emission by the fluorescent agent, and identifying modulating compounds as those test compounds that affect the emission of light by the florescent agent in comparison to the emission of light by the fluorescent agent in the absence of the test compound.
  • the MCCS1 interacting protein may be immobilized and MCCS1 may be labelled in the assay.
  • host cells for example, esr1-1 yeast cells
  • MCCS1-encoding DNA as is described in Example 4.
  • the esr1-1 yeast strain is normally sensitive to treatment with ultraviolet (UV) light, but esr1-1 yeast cells expressing MCCS1 or ATR are no longer sensitive to treatment with UV light.
  • the transformed yeast cells are exposed to test compounds and the effect of the test compounds on UV sensitivity ofthe transformed host cell is determined.
  • Test compounds that are inhibitors of MCCS1 or ATR activity restore UV sensitivity to the MCCS1 transformed esr1-1 cells.
  • esr1-1 tell double mutant yeast cells are used as host cells instead of esr1-1 yeast cells.
  • the TEL1 gene is homologous to ATM and the TEL1 mutation is described in Morrow, et al., Cell,
  • MCCS1 and ATM are both involved in meiosis I checkpoints. Since MCCS1 is demonstrated herein to have kinase activity, assays were performed to determine if ATM possessed kinase activity. To determine the kinase activity of
  • MRC-5 cell extracts were prepared by lysis of a 10cm plate of log-phase cells in 0.5 ml of Lysis Buffer I (50 mM NaPO 4 , pH 7.2; 0.5 % TritonX-100;
  • Preclearing was done by adding 10 ⁇ g purified rabbit IgG (Zymed) and 30 ⁇ l Protein A Agarose slurry (Pierce) followed by incubation at 4°C for 60 minutes while rocking. To the precleared lysates, 10 ⁇ g of affinity purified 6076 antisera (or 10 ⁇ g 6076 pre-blocked with 0.04 mg P45 peptide for 30 min.) was added and incubated on ice for 60 minutes. Immunoprecipitates were collected by addition of 30 ⁇ l Protein A agarose slurry and incubated with rocking at 4°C for 30 minutes followed by four washes in Lysis Buffer I.

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Abstract

L'invention concerne d'une manière générale des gènes codant des protéines relatives à la phosphatidylinositol kinase (PIK) du point de contrôle du cycle cellulaire, ces protéines étant essentielles aux réponses de dommages de l'ADN dans les cellules. Ces kinases relatives à PIK sont nécessaires dans les chemins régulateurs qui arrêtent le cycle cellulaire suite à des dommages de l'ADN afin de permettre la réparation de l'ADN avant une mitose ou un début de réplication de l'ADN. Plus particulièrement, l'invention concerne une nouvelle kinase relative à PIK du point de contrôle du cycle des cellules humaines, MCCS1, et des séquences polynucléotidiques codant MCSS1. Des dosages permettant d'identifier des modulateurs de MCCS1 utiles par exemple en chimiothérapie et comme adjuvant de radiation sont également décrits dans l'invention. Celle-ci décrit également des dosages permettant d'identifier des modulateurs de la protéine relative à phosphatidylinositol kinase du point de contrôle du cycle cellulaire, lesquels ont reçu l'identification ATM.
PCT/US1996/019337 1995-11-16 1996-11-18 Materiaux de kinase relatifs a la phosphatidylinositol kinase du point de controle du cycle cellulaire, et procedes Ceased WO1997018323A2 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
AU14611/97A AU1461197A (en) 1995-11-16 1996-11-18 Cell cycle checkpoint pik-related kinase materials and methods
IL12130696A IL121306A0 (en) 1995-11-16 1996-11-18 Cell cycle checkpoint pik-related kinase materials and methods
FI973005A FI973005A7 (fi) 1995-11-16 1996-11-18 Solusyklin kontrollikohdan PIK-sukuisia kinaasimateriaaleja ja menetel miä
EP96945181A EP0807169A3 (fr) 1995-11-16 1996-11-18 Materiaux de kinase relatifs a la phosphatidylinositol kinase du point de controle du cycle cellulaire, et procedes
JP51918097A JP2002515732A (ja) 1995-11-16 1996-11-18 細胞周期チェックポイントｐｉｋ関連キナーゼ物質及び方法
SK1115-97A SK111597A3 (en) 1995-11-16 1996-11-18 Cell-cycle checkpoint phosphatidylinositol- (pik-) related kinases, genes coding therefor and methods for assaying and modulating enzymatic activity
MX9705466A MX9705466A (es) 1995-11-16 1996-11-18 Materiales y metodos de quinasa relacionada con fosfatidilinositolquinasa de punto de control del ciclo celular.
HU0002207A HUP0002207A2 (hu) 1996-10-21 1996-11-18 A sejtciklus szabályozási pont PIK-kel rokon kínázai és eljárás előállításukra
NO973279A NO973279L (no) 1995-11-16 1997-07-15 PIK-beslektede kinasematerialer og fremgangsmåter for cellesykluskontrollpunkt

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US55866695A 1995-11-16 1995-11-16
US73129696A 1996-02-27 1996-02-27
US72530496A 1996-10-21 1996-10-21
US08/558,666 1996-10-21
US08/007,312 1996-10-21
US08/725,304 1996-10-21

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WO1997018323A2 true WO1997018323A2 (fr) 1997-05-22
WO1997018323A3 WO1997018323A3 (fr) 1997-10-09

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AU (1) AU1461197A (fr)
IL (1) IL121306A0 (fr)
NO (1) NO973279L (fr)
PL (1) PL322876A1 (fr)
WO (1) WO1997018323A2 (fr)

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999002653A1 (fr) * 1997-07-11 1999-01-21 Trustees Of The University Of Pennsylvania Acide nucleique codant une nouvelle proteine induite par chimiotherapie, et ses procedes d'utilisation
WO1999011795A1 (fr) * 1997-09-05 1999-03-11 Icos Corporation Materiels de proteine-kinase point de controle du cycle cellulaire, effecteur de chk1 mammalien et methodes
WO1999025843A3 (fr) * 1997-10-22 1999-08-05 Scripps Research Inst Kinase humaine de controle, hcds1, compositions et procedes
WO1999004266A3 (fr) * 1997-07-16 1999-08-19 Kudos Pharm Ltd Techniques, methodes et procedes therapeutiques
WO1999015157A3 (fr) * 1997-09-25 1999-09-23 Univ British Columbia Inhibiteurs des points de controle g2 et dosage
US6071691A (en) * 1998-04-27 2000-06-06 Oregon Health Science University Materials and methods for modulating differentiation
EP0826031A4 (fr) * 1995-05-16 2000-09-06 Univ Ramot Gene de l'ataxia-telangiectasie et son organisation genomique
EP0826033A4 (fr) * 1995-05-16 2000-09-06 Univ Ramot Gene de l'ataxie-telangiectasie
WO2000047760A3 (fr) * 1999-02-10 2000-11-30 St Jude Childrens Res Hospital Modulation d'atm kinase utile a des fins de criblage et therapeutiques
US6387640B1 (en) 1999-02-10 2002-05-14 St. Jude Children's Research Hospital ATM kinase modulation for screening and therapies
US6670167B1 (en) 1999-11-01 2003-12-30 Agouron Pharmaceuticals, Inc. Catalytic domain of the human effector cell cycle checkpoint protein kinase materials and methods for identification of inhibitors thereof
WO2004038008A3 (fr) * 2002-10-25 2006-03-23 Univ Massachusetts Modulation de la proliferation cellulaire
US7049313B2 (en) 2002-02-25 2006-05-23 Kudos Pharmaceuticals Ltd. ATM inhibitors
EP0856058B1 (fr) * 1995-09-06 2006-07-26 ICOS Corporation Genes de point de controle a cycle cellulaire
US7105518B2 (en) 2001-08-14 2006-09-12 Cancer Research Technology Limited Thiopyrane-4-ones as DNA protein kinase inhibitors
US7226918B2 (en) 2001-08-14 2007-06-05 Cancer Research Technology Limited DNA-PK inhibitors
US7402607B2 (en) 2004-09-20 2008-07-22 Kudos Pharmaceuticals Limited DNA-PK inhibitors
US7429660B2 (en) 2003-08-13 2008-09-30 Kudos Pharmaceuticals Limited ATM inhibitors
US7642254B2 (en) 2005-02-09 2010-01-05 Kudos Pharmaceuticals Limited ATM inhibitors
US7696203B2 (en) 2005-04-15 2010-04-13 Kudos Pharmaceuticals Limited DNA-PK inhibitors

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9518220D0 (en) * 1995-09-06 1995-11-08 Medical Res Council Checkpoint gene

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0826033A4 (fr) * 1995-05-16 2000-09-06 Univ Ramot Gene de l'ataxie-telangiectasie
EP0826031A4 (fr) * 1995-05-16 2000-09-06 Univ Ramot Gene de l'ataxia-telangiectasie et son organisation genomique
EP0856058B1 (fr) * 1995-09-06 2006-07-26 ICOS Corporation Genes de point de controle a cycle cellulaire
WO1999002653A1 (fr) * 1997-07-11 1999-01-21 Trustees Of The University Of Pennsylvania Acide nucleique codant une nouvelle proteine induite par chimiotherapie, et ses procedes d'utilisation
US7138236B1 (en) 1997-07-16 2006-11-21 Kudos Pharmaceuticals Limited Interactions of ATM, ATR or DAN-PK with p53
WO1999004266A3 (fr) * 1997-07-16 1999-08-19 Kudos Pharm Ltd Techniques, methodes et procedes therapeutiques
WO1999011795A1 (fr) * 1997-09-05 1999-03-11 Icos Corporation Materiels de proteine-kinase point de controle du cycle cellulaire, effecteur de chk1 mammalien et methodes
WO1999015157A3 (fr) * 1997-09-25 1999-09-23 Univ British Columbia Inhibiteurs des points de controle g2 et dosage
WO1999025843A3 (fr) * 1997-10-22 1999-08-05 Scripps Research Inst Kinase humaine de controle, hcds1, compositions et procedes
US6071691A (en) * 1998-04-27 2000-06-06 Oregon Health Science University Materials and methods for modulating differentiation
WO2000047760A3 (fr) * 1999-02-10 2000-11-30 St Jude Childrens Res Hospital Modulation d'atm kinase utile a des fins de criblage et therapeutiques
US6348311B1 (en) 1999-02-10 2002-02-19 St. Jude Childre's Research Hospital ATM kinase modulation for screening and therapies
US6387640B1 (en) 1999-02-10 2002-05-14 St. Jude Children's Research Hospital ATM kinase modulation for screening and therapies
US6670167B1 (en) 1999-11-01 2003-12-30 Agouron Pharmaceuticals, Inc. Catalytic domain of the human effector cell cycle checkpoint protein kinase materials and methods for identification of inhibitors thereof
US7674823B2 (en) 2001-08-14 2010-03-09 Cancer Research Technology Limited DNA-PK inhibitors
US7105518B2 (en) 2001-08-14 2006-09-12 Cancer Research Technology Limited Thiopyrane-4-ones as DNA protein kinase inhibitors
US7226918B2 (en) 2001-08-14 2007-06-05 Cancer Research Technology Limited DNA-PK inhibitors
US7049313B2 (en) 2002-02-25 2006-05-23 Kudos Pharmaceuticals Ltd. ATM inhibitors
WO2004038008A3 (fr) * 2002-10-25 2006-03-23 Univ Massachusetts Modulation de la proliferation cellulaire
US7429660B2 (en) 2003-08-13 2008-09-30 Kudos Pharmaceuticals Limited ATM inhibitors
US7402607B2 (en) 2004-09-20 2008-07-22 Kudos Pharmaceuticals Limited DNA-PK inhibitors
US7732483B2 (en) 2004-09-20 2010-06-08 Kudos Pharmaceuticals Limited DNA-PK inhibitors
US7642254B2 (en) 2005-02-09 2010-01-05 Kudos Pharmaceuticals Limited ATM inhibitors
US7696203B2 (en) 2005-04-15 2010-04-13 Kudos Pharmaceuticals Limited DNA-PK inhibitors

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AU1461197A (en) 1997-06-05
CN1199420A (zh) 1998-11-18
IL121306A0 (en) 1998-01-04
WO1997018323A3 (fr) 1997-10-09
NO973279L (no) 1997-09-16
PL322876A1 (en) 1998-03-02
NO973279D0 (no) 1997-07-15

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