JP6473461B2 - Brca1欠損癌または耐性癌の治療 - Google Patents
Brca1欠損癌または耐性癌の治療 Download PDFInfo
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- JP6473461B2 JP6473461B2 JP2016558595A JP2016558595A JP6473461B2 JP 6473461 B2 JP6473461 B2 JP 6473461B2 JP 2016558595 A JP2016558595 A JP 2016558595A JP 2016558595 A JP2016558595 A JP 2016558595A JP 6473461 B2 JP6473461 B2 JP 6473461B2
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Description
本出願は2014年3月26日に出願された米国仮出願第61/970,737号の利益を主張し、その全体は参照することによりすべての目的のために本明細書に援用される。
ファイル48440−541001WO_ST25.TXT(2015年3月24日に生成、1,055バイト、マシンフォーマットIBM−PC、MS−Windowsオペレーティングシステム)中に書き込まれた配列リストは、参照することにより本明細書に援用される。
本発明は、National Institute of Cancer(NCI)によって授与された補助金番号CA 127541及びNational Institutes of Health(NIH)によって授与された補助金番号P30CA033572下の政府助成により行なわれた。米国政府は本発明において一定の権利を有する。
「患者」「被験体」、「それを必要とする患者」、及び「それを必要とする被験体」は本明細書において互換的に使用され、COH29または本明細書において論じられるような他の抗癌剤と組み合わせたCOH29の投与によって治療できる疾患または病態を患うまたはそれらを起こしやすい生物体を指す。複数の実施形態において、疾患または病態は癌である。被験体の非限定例には、ヒト、他の哺乳類、ウシ属の動物、ラット、マウス、イヌ、サル、ヤギ、ヒツジ、ウシ、シカ及び他の非哺乳類動物が含まれる。複数の実施形態において、患者はヒトである。
第1の態様は、それを必要とする被験体において癌を治療する方法である。方法は、効果的な量のCOH29を被験体へ投与することを含む。被験体は、本明細書において説明されるように、BRCA1欠損被験体、PARP1阻害剤耐性被験体、またはDNA損傷性抗癌剤耐性被験体である。したがって、複数の実施形態において、被験体はBRCA1欠損被験体である。被験体はPARP1阻害剤耐性被験体であり得る。被験体はDNA損傷性抗癌剤耐性被験体であり得る。複数の実施形態において、被験体は、BRCA1欠損被験体、PARP1阻害剤耐性被験体、またはDNA損傷性抗癌剤耐性被験体のうちの少なくとも1つである。したがって、被験体は、BRCA1欠損被験体、及びPARP1阻害剤耐性被験体またはDNA損傷性抗癌剤耐性被験体のうちの少なくとも1つであり得る(すなわち、癌は、BRCA1欠損、及びPARP1阻害剤またはDNA損傷性抗癌剤のうちの少なくとも1つへの耐性を有する)。
マウスにおける実験は、City of HopeのIACUCによって承認されたプロトコル下で行った。HCC1937細胞及びHCC1937+BRCA1細胞が緩慢に増殖する腫瘍を形成するので、それらをMATRIGEL(商標)(Becton−Dickinson Biosciences)を使用して移植した。腫瘍を確立するために、50%のMATRIGEL(商標)を含有する200μLの無血清培地中の4×106細胞を、1ペアの8週齢のメスNSGマウスの鼠径部の周囲の乳房脂肪体の中へ注射した。一旦初発腫瘍が直径13mmに到達したならば、それらを解剖し、3mm片へとミンスし、実験用マウスの乳房脂肪体の鼠径部の中へ移植した。腫瘍を28日の期間にわたって測定し、各々の時間点について、スチューデントのt検定を使用して、30%のソルトール中の400mg/kgのCOH29による毎日の強制投与と対応するベヒクル対照との間の統計的有意性を決定する。0.05未満のp値(両側)は統計的有意性を示すと判断した。
(1) Hehlmann R. Current CML therapy: progress and dilemma. Leukemia. 2003;17:1010−2; (2) Shewach DS, Lawrence TS. Antimetabolite radiosensitizers. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2007;25:4043− 50; (3) Reichard P, Ehrenberg A. Ribonucleotide reductase−a radical enzyme. Science. 1983;221:514−9; (4) Xue L, Zhou B, Liu X, Qiu W, Jin Z, Yen Y. Wild−type p53 regulates human ribonucleotide reductase by protein−protein interaction with p53R2 as well as hRRM2 subunits. Cancer Res. 2003;63:980−6; (5) Shao J, Zhou B, Zhu L, Qiu W, Yuan YC, Xi B, et al.
In vitro characterization of enzymatic properties and inhibition of the p53R2 subunit of human ribonucleotide reductase. Cancer Res. 2004;64:1−6; (6) Young CW, Hodas S. Hydroxyurea: Inhibitory Effect on DNA Metabolism. Science. 1964; 146:1172−4; (7) Platt OS. Hydroxyurea for the treatment of sickle cell anemia. The New England Journal of Medicine. 2008;358:1362−9; (8) Zhou B, Su L, Hu S, Hu W, Yip ML, Wu J, et al. A small−molecule blocking ribonucleotide reductase holoenzyme formation inhibits cancer cell growth and overcomes drug resistance. Cancer Res. 2013;73:6484−93; (9) Helleday T, Petermann E, Lundin C, Hodgson B, Sharma RA. DNA repair pathways as targets for cancer therapy. Nature Reviews Cancer. 2008;8:193− 204; (10) Balajee AS, Bohr VA. Genomic heterogeneity of nucleotide excision repair. Gene. 2000;250:15−30; (11) Rouleau M, Patel A, Hendzel MJ, Kaufmann SH, Poirier GG. PARP inhibition: PARP1 and beyond. Nature Reviews Cancer. 2010;10:293−301; (12) Yelamos J, Farres J, Llacuna L, Ampurdanes C, Martin−Caballero J. PARP−1 and PARP−2: New players in tumour development. American Journal of Cancer Research. 2011;1:328−46; (13) D’Amours D, Desnoyers S, D’Silva I, Poirier GG. Poly(ADP−ribosyl)ation reactions in the regulation of nuclear functions. The Biochemical Journal. 1999;342 (Pt 2):249−68; (14) Simonin F, Menissier−de Murcia J, Poch O, Muller S, Gradwohl G, Molinete M, et al. Expression and site− directed mutagenesis of the catalytic domain of human poly(ADP−ribose)polymerase in Escherichia coli. Lysine 893 is critical for activity. J Biol Chem. 1990;265:19249−56; (15) Gottipati P, Vischioni B, Schultz N, Solomons J, Bryant HE, Djureinovic T, et al. Poly(ADP−ribose) polymerase is hyperactivated in homologous recombination−defective cells. Cancer Res. 2010;70:5389−98; (16) Moeller BJ, Pasqualini R, Arap W. Targeting cancer−specific synthetic lethality in double−strand DNA break repair. Cell Cycle (Georgetown, Tex). 2009;8:1872−6; (17) Curtin NJ. DNA repair dysregulation from cancer driver to therapeutic target. Nature Reviews Cancer. 2012;12:801−17; (18) Miknyoczki SJ, Jones−Bolin S, Pritchard S, Hunter K, Zhao H, Wan W, et al. Chemopotentiation of temozolomide, irinotecan, and cisplatin activity by CEP− 6800, a poly(ADP−ribose) polymerase inhibitor. Mol Cancer Ther. 2003;2:371−82; (19) Mukhopadhyay A, Plummer ER, Elattar A, Soohoo S, Uzir B, Quinn JE, et al. Clinicopathological features of homologous recombination−deficient epithelial ovarian cancers: sensitivity to PARP inhibitors, platinum, and survival. Cancer Res. 2012;72:5675−82; (20) Sessa C. Update on PARP1 inhibitors in ovarian cancer. Ann Oncol. 2011 ;22 Suppl 8:viii72− viii6; (21) Chung YM, Park SH, Tsai WB, Wang SY, Ikeda MA, Berek JS, et al. F0XO3 signalling links ATM to the p53 apoptotic pathway following DNA damage. Nature Communications. 2012;3:1000; (22) Tsai WB, Chung YM, Takahashi Y, Xu Z, Hu MC. Functional interaction between FOXO3a and ATM regulates DNA damage response. Nature Cell Biology. 2008;10:460−7; (23) Bennardo N, Cheng A, Huang N, Stark JM. Alternative− NHEJ is a mechanistically distinct pathway of mammalian chromosome break repair. PLoS Genetics. 2008;4:el000110; (24) Un F, Qi C, Prosser M, Wang N, Zhou B, Bronner C, et al. Modulating ICBP90 to suppress human ribonucleotide reductase M2 induction restores sensitivity to hydroxyurea cytotoxicity. Anticancer Res. 2006;26:2761−7; (25) Westerfield M. THE ZEBRAFISH BOOK : A GUIDE FOR THE LABORATORY USE OF ZEBRAFISH (BRACHYDANIO RERIO). Eugene, OR: M. Westerfield; 1993; (26) Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nature Methods. 2012;9:671−5; (27) Irizarry RA, Hobbs B, Collin F, Beazer−Barclay YD, Antonellis KJ, Scherf U, et al. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics. 2003;4:249−64; (28) Benjamini Y, Hochberg Y. CONTROLLING THE FALSE DISCOVERY RATE − A PRACTICAL AND POWERFUL APPROACH TO MULTIPLE TESTING. JR Stat Soc Ser B− Methodol. 1995;57:289−300; (29) Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nature Genetics. 2000;25:25−9; (30) Ivshina AV, George J, Senko O, Mow B, Putti TC, Smeds J, et al. Genetic reclassification of histologic grade delineates new clinical subtypes of breast cancer. Cancer Res. 2006;66:10292−301; (31) R Development Core Team. A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing; 2013; (32) Wooster R, Weber BL. Breast and ovarian cancer. The New England Journal of Medicine. 2003;348:2339−47; (33) DelloRusso C, Welcsh PL, Wang W, Garcia RL, King MC, Swisher EM. Functional characterization of a novel BRCA1−null ovarian cancer cell line in response to ionizing radiation. Mol Cancer Res. 2007;5:35−45; (34) Tomlinson GE, Chen TT, Stastny VA, Virmani AK, Spillman MA, Tonk V, et al. Characterization of a breast cancer cell line derived from a germ−line BRCA1 mutation carrier. Cancer Res. 1998;58
:3237−42; (35) Anglesio MS, Arnold JM, George J, Tinker AV, Tothill R, Waddell N, et al. Mutation of ERBB2 provides a novel alternative mechanism for the ubiquitous activation of RAS−MAPK in ovarian serous low malignant potential tumors. Mol Cancer Res. 2008;6:1678−90; (36) Ziegler−Skylakakis K, Schwarz LR, Andrae U. Microsome− and hepatocyte−mediated mutagenicity of hydroxyurea and related aliphatic hydroxamic acids in V79 Chinese hamster cells. Mutat Res. 1985;152:225−31; (37) Friedrisch JR, Pra D, Maluf SW, Bittar CM, Mergener M, Pollo T, et al. DNA damage in blood leukocytes of individuals with sickle cell disease treated with hydroxyurea. Mutat Res. 2008;649:213−20; (38) Houtgraaf JH, Versmissen J, van der Giessen WJ. A concise review of DNA damage checkpoints and repair in mammalian cells. Cardiovascular Revascularization Medicine : including Molecular Interventions. 2006;7:165−72; (39) Abbas T, Keaton MA, Dutta A. Genomic instability in cancer. Cold Spring Harbor Perspectives in Biology. 2013;5:a012914; (40) Rabik CA, Dolan ME. Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treatment Reviews. 2007;33:9−23; (41) Selvakumaran M, Pisarcik DA, Bao R, Yeung AT, Hamilton TC. Enhanced cisplatin cytotoxicity by disturbing the nucleotide excision repair pathway in ovarian cancer cell lines. Cancer Res. 2003;63:1311−6; (42) Pendleton KP, Grandis JR. Cisplatin−Based Chemotherapy Options for Recurrent and/or Metastatic Squamous Cell Cancer of the Head and Neck. Clinical Medicine Insights Therapeutics. 2013;2013; (43) Cheng H, Zhang Z, Borczuk A, Powell CA, Balajee AS, Lieberman HB, et al. PARP inhibition selectively increases sensitivity to cisplatin in ERCC1−low non−small cell lung cancer cells. Carcinogenesis. 2013;34:739−49; (44) Tassone P, Di Martino MT, Ventura M, Pietragalla A, Cucinotto I, Calimeri T, et al. Loss of BRCA1 function increases the antitumor activity of cisplatin against human breast cancer xenografts in vivo. Cancer Biology & Therapy. 2009;8:648−53; (45) Haaf T, Golub El, Reddy G, Radding CM, Ward DC. Nuclear foci of mammalian Rad51 recombination protein in somatic cells after DNA damage and its localization in synaptonemal complexes. Proc Natl Acad Sci U S A. 1995;92:2298−302; (46) Baumann P, Benson FE, West SC. Human Rad51 protein promotes ATP−dependent homologous pairing and strand transfer reactions in vitro. Cell. 1996;87:757−66; (47) Petermann E, Orta ML, Issaeva N, Schultz N, Helleday T. Hydroxyurea−stalled replication forks become progressively inactivated and require two different RAD51−mediated pathways for restart and repair. Molecular Cell. 2010;37:492−502; (48) Hegan DC, Lu Y, Stachelek GC, Crosby ME, Bindra RS, Glazer PM. Inhibition of poly(ADP−ribose) polymerase down−regulates BRCA1 and RAD51 in a pathway mediated by E2F4 and p130. Proc Natl Acad Sci USA. 2010;107:2201−6; (49) Connell PP, Siddiqui N, Hoffman S, Kuang A, Khatipov EA, Weichselbaum RR, et al. A hot spot for RAD51C interactions revealed by a peptide that sensitizes cells to cisplatin. Cancer Res. 2004;64:3002−5; (50) Sak A, Stueben G, Groneberg M, Bocker W, Stuschke M. Targeting of Rad51−dependent homologous recombination: implications for the radiation sensitivity of human lung cancer cell lines. British Journal of Cancer. 2005;92:1089−97; (51) Zhu J, Zhou L, Wu G, Konig H, Lin X, Li G, et al. A novel small molecule RAD51 inactivator overcomes imatinib− resistance in chronic myeloid leukaemia. EMBO Molecular Medicine. 2013;5:353−65; (52) Helleday T. Homologous recombination in cancer development, treatment and development of drug resistance. Carcinogenesis. 2010;31:955−60; (53) Maacke H, Opitz S, Jost K, Hamdorf W, Henning W, Kruger S, et al. Over−expression of wild−type Rad51 correlates with histological grading of invasive ductal breast cancer. International jJournal of Cancer. 2000;88:907−13; (54) Montoni A, Robu M, Pouliot E, Shah GM. Resistance to PARP−Inhibitors in Cancer Therapy. Frontiers in Pharmacology. 2013;4:18; (55) Aly A, Ganesan S. BRCAl, PARP, and 53BP1: conditional synthetic lethality and synthetic viability. Journal of Molecular Cell Biology. 2011;3:66−74.
本明細書において開示される対象物の実施形態には以下のものが含まれる。
Claims (13)
- 前記医薬組成物が前記被験体におけるDNA修復を阻害する、請求項1に記載の医薬組成物。
- 前記医薬組成物が、前記被験体における、塩基除去修復(BER)、ヌクレオチド除去修復(NER)または二本鎖DNA切断修復を阻害する、請求項1に記載の医薬組成物。
- 前記医薬組成物が、前記被験体における、γ−H2AXタンパク質の活性または発現を増加させる、請求項1に記載の医薬組成物。
- 前記医薬組成物が、前記被験体における、Rad51タンパク質の活性または発現を低下させる、請求項1に記載の医薬組成物。
- 前記医薬組成物が、前記被験体における、BRCA1タンパク質の活性または発現を低下させる、請求項1に記載の医薬組成物。
- 前記医薬組成物が、前記被験体における、PARP1タンパク質の活性または発現を低下させる、請求項1に記載の医薬組成物。
- 前記DNA損傷性抗癌剤が化学療法DNA損傷性薬剤である、請求項8に記載の医薬組成物。
- 前記化学療法DNA損傷性薬剤がアルキル化剤である、請求項9に記載の医薬組成物。
- 前記アルキル化剤が、エチレンイミン、メチルメラミン、ニトロソウレア、ナイトロジェンマスタード、ブスルファン、シクロフォスファミドまたはプロカルバジンである、請求項10に記載の医薬組成物。
- 前記化学療法DNA損傷性薬剤が、トポイソメラーゼI剤、トポイソメラーゼII剤、カンプトセシン、イリノテカン、トポテカン、シスプラチン、カルボプラチン、オキサリプラチン、アドリアマイシン、ドキソルビシン、エトポシド、一本鎖切断剤、BCNUカルマスティン、CCNU、DTIC、サイトキサン、イフォスファミド、ブレオマイシンまたはマイトマイシンCである、請求項8に記載の医薬組成物。
- 前記DNA損傷性抗癌剤が、シスプラチン、ゲムシタビンまたはγ線照射である、請求項12に記載の医薬組成物。
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WO2015148839A1 (en) | 2014-03-26 | 2015-10-01 | City Of Hope | Treatment of brca1-defective cancer or resistant cancers |
KR20190111116A (ko) * | 2017-02-06 | 2019-10-01 | 시티 오브 호프 | 암의 치료 |
CN108663519A (zh) * | 2017-04-21 | 2018-10-16 | 江苏希摩生物科技有限公司 | 快速预测和提高BRCA1/2野生型卵巢癌细胞对Olaparib敏感性的方法 |
WO2019014315A1 (en) * | 2017-07-11 | 2019-01-17 | Cyteir Therapeutics, Inc. | RAD51 INHIBITORS |
WO2019089216A1 (en) * | 2017-11-01 | 2019-05-09 | Dana-Farber Cancer Institute, Inc. | Methods of treating cancers |
CN114848848B (zh) * | 2022-04-13 | 2023-05-09 | 重庆文理学院 | 一种逆转非小细胞肺癌耐药性的基因药物 |
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US4177263A (en) | 1972-02-28 | 1979-12-04 | Research Corporation | Anti-animal tumor method |
US4584316A (en) | 1983-03-25 | 1986-04-22 | Research Corporation | Palladium anti-cancer complexes |
US4911920A (en) | 1986-07-30 | 1990-03-27 | Alcon Laboratories, Inc. | Sustained release, comfort formulation for glaucoma therapy |
FR2588189B1 (fr) | 1985-10-03 | 1988-12-02 | Merck Sharp & Dohme | Composition pharmaceutique de type a transition de phase liquide-gel |
ATE141502T1 (de) | 1991-01-15 | 1996-09-15 | Alcon Lab Inc | Verwendung von karrageenan in topischen ophthalmologischen zusammensetzungen |
US5212162A (en) | 1991-03-27 | 1993-05-18 | Alcon Laboratories, Inc. | Use of combinations gelling polysaccharides and finely divided drug carrier substrates in topical ophthalmic compositions |
FR2682110B1 (fr) | 1991-10-02 | 1995-05-24 | Atta | Ligands amphiphiles perfluoroalkyles leurs complexes metalliques et leurs utilisations dans des preparations a usage therapeutique. |
CA2708149A1 (en) * | 2007-12-13 | 2009-06-18 | Novartis Ag | Combinations of therapeutic agents for treating cancer |
US7956076B2 (en) * | 2008-04-08 | 2011-06-07 | City Of Hope | Ribonucleotide reductase inhibitors and methods of use |
US8372983B2 (en) | 2008-04-08 | 2013-02-12 | City Of Hope | Ribonucleotide reductase inhibitors and methods of use |
AU2013214846B2 (en) * | 2012-02-01 | 2017-09-07 | City Of Hope | Ribonucleotide reductase inhibitors and methods of use |
WO2015148839A1 (en) | 2014-03-26 | 2015-10-01 | City Of Hope | Treatment of brca1-defective cancer or resistant cancers |
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2015
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- 2015-03-26 CA CA2940656A patent/CA2940656A1/en not_active Abandoned
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IL247940A0 (en) | 2016-11-30 |
CN106132203A (zh) | 2016-11-16 |
AU2015235929A1 (en) | 2016-09-01 |
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WO2015148839A1 (en) | 2015-10-01 |
CN106132203B (zh) | 2020-05-15 |
US20180185338A1 (en) | 2018-07-05 |
US9931322B2 (en) | 2018-04-03 |
JP2017516748A (ja) | 2017-06-22 |
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