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WO 2014/170441 Al 23 October 2014 (23.10.2014) P O PCT

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WO 2014/170441 Al 23 October 2014 (23.10.2014) P O PCT (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2014/170441 Al 23 October 2014 (23.10.2014) P O PCT (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C12N 15/11 (2006.01) A61P 35/00 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/712 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (21) International Application Number: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/EP2014/057904 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (22) International Filing Date: KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, 17 April 2014 (17.04.2014) MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (25) Filing Language: English SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, (26) Publication Language: English TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 133055 18.6 19 April 2013 (19.04.2013) EP (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicants: DNA THERAPEUTICS [FR/FR]; Pepiniere GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, Genopole Entreprise, 4 rue Pierre Fontaine, F-91058 Evry UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, Cedex (FR). INSTITUT CURIE [FR/FR]; 26 rue d'Ulm, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, F-75248 Paris cedex 05 (FR). EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, (72) Inventors: DUTRELX, Marie; 62 rue de Chalais, F-94240 TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, L'Hay-les Roses (FR). SUN, Jian-Sheng; 24 place du KM, ML, MR, NE, SN, TD, TG). President J. F. Kennedy, F-94100 Saint Maur des Fosses (FR). Published: (74) Agents: GALLOIS, Valerie et al; Becker & Associes, 25 — with international search report (Art. 21(3)) rue Louis Le Grand, F-75002 Paris (FR). — with sequence listing part of description (Rule 5.2(a)) o - (54) Title: INHIBITION OF DNA DAMAGE REPAIR BY ARTIFICIAL ACTIVATION OF PARP WITH OLIGONUCLEOTIDE © MOLECULES (57) Abstract: The present application relates to a new class of PARP inhibitors and their uses as a drug, especially as for use in a cancer therapy. These new PARP inhibitors include a double stranded portion with a nick or a gap on one strand and the tethered 5' S and 3' ends of two extremities of the double stranded portion. INHIBITION OF DNA DAMAGE REPAIR BY ARTIFICIAL ACTIVATION OF PARP WITH OLIGONUCLEOTIDE MOLECULES FIELD OF THE INVENTION The present invention relates to molecules, compositions and methods of inhibiting the DNA damage repair in mammalian cells. Accordingly, the invention relates to compositions and methods for treating proliferative disorders. BACKGROUND OF THE INVENTION To overcome DNA damage, cells have evolved mechanisms to detect DNA lesions, signal their presence and promote their repair. The wide diversity of types of DNA lesion generally necessitates multiple and specialized DNA-repair mechanisms. Although responses to different types of DNA lesions differ, most occur via signal transduction cascades involving post-translational modifications, such as ubiquitination, phosphorylation, acetylation and poly(ADP-ribosy)lation (PAR also called PARylation). Key regulators within these signaling cascades such as the phosphatidylinositol 3-kinase-related kinases (PI3K) ATM, ATR or DNA-PK, and the poly(ADP-ribose) polymerase (PARP), are activated via direct or indirect interaction with double-strand breaks (DSB) and single-strand breaks (SSB). The most toxic DNA damage to the cell are DSB, which, if left unrepaired, lead to loss of chromosome fragments and cell death. Cells have two major pathways to repair DSB: homologous recombination (HR) and non-homologous end joining (NHEJ). These pathways are complementary and operate optimally during the S and G2 phases of the cell cycle for HR and throughout all cell cycle for NHEJ pathway. Thus, during S and G2 phases of the cell cycle, DSB are preferentially repaired by homologous recombination (HR) between sister chromatins. An important regulatory step that determines the choice between the NHEJ and HR pathways is the process of DSB by the MRE 11-RAD50-NBS 1 complex (MRN), in conjunction with other factors. After resection of DSB ends, the resulting single-strand DNA ends are coated with Replication Protein A (RPA) and then RAD5 1 with the help of RAD52, BReast CAncer 2 (BRCA2) and Fanconi anemia (FANC) proteins; these proteins promote invasion and strand exchange with the homologous region on the sister chromatin. Thereafter, repair proceeds either via the double Holliday junction model DSB repair (DSBR) pathway or via the synthesis-dependent strand-annealing (SDSA) pathway. In mammalian cells, NHEJ is the major pathway for repairing breaks not associated with replication. NHEJ involves the direct rejoining of two damaged DNA ends in a sequence-independent manner: DNA ends are first bound by the Ku70/ku80 heterodimer, which recruits and activates the catalytic subunit, DNA-PKcs, to form the DNA-PK holoenzyme. Broken DNA ends are then processed and ligated by a set of enzymes including Artemis, polynucleotide kinase (PNK), X-ray cross- complementing 4 (XRCC4), and Ligase IV. If the classical mechanism of NHEJ is impeded, an alternative end-joining pathway operates that involves factors of HR and SSB repair, including MRN complex, PARP-1, X-ray cross-complementing 1 (XRCCl) and DNA Ligase I or III. Although less harmful than DSB, SSB are toxic. One of the most common sources of SSB is oxidative attack by endogenous reactive oxygen species (ROS). In the case of free radicals from hydrogen peroxide (H2O2), a physiologically relevant source of ROS, SSB occur three orders of magnitude more frequently than DSB. Following exposure to ionizing radiation, SSB are 25 times more abundant than DSB. They are primarily detected by PARP-1 although other members of the PARP super family may contribute. Binding of PARP to SSB triggers poly(ADP-ribosy)lation of numerous nuclear proteins including PARP itself. These modifications in turn promote the binding of XRCCl, which acts as a molecular scaffold for SSB repair components. Therefore PARP, which binds to DSB with a greater affinity than that for its binding to SSB is involved in repair of both, whereas the recruitment of DNA-PK by Ku is strictly dependent on DSB, and seems to be involved in DSB repair only. The outcome of DNA damage signaling is, literally, a matter of life or death. Depending on the severity of the DNA damage, the cell will either repair the damage to enable it to continue dividing, or enter apoptosis. The understanding of the dynamics of the repair proteins has been greatly advanced through the use of various types of DNA substrates in biochemical assays. In particular short interter ng double-stranded DNA molecules (siDNA) that c DSB damage (called Dbait) induce a partial damage response in cells and can be used to analyze the early steps of repair protein recruitment in vivo. Dbait molecules activate DNA- P kinase and have o significant effect on other PI3K kinases. In the course of this response, several nuclear DNA-PK targets, such s p53, Rpa32 or H2AX, are extensively phosphorylated. The activation of DNA-PK prevents recognition of further DSB and inhibits not o l the NHEJ, which directly depends upon DNA-PK, but also R pathways. Such Dbait molecules have been described and developed as new drugs for treating proliferative disorders, i particular cancers (WO 2005/040378: O 2008/034866: WO 2008/084087). Even if the Dbait molecules confirm their very promising status, there is a permanent need to improve the cancer therapy and to provide new targets and tools for treating proliferative disorders. SUMMARY OF THE INVENTION The present invention provides a new class of PARP inhibitors called Pbait. The present invention relates to a molecule comprising a deoxyribonucleotide double- stranded portion of 12 to 200 bp, wherein it has preferably less than 80% sequence identity to any gene in a human genome, it has a single strand break or a gap on one strand, preferably, in the middle part of said double-stranded portion and the 5' and 3' ends at both extremities of said double-stranded portion are tethered by a linker. Preferably, the double-stranded portion is from 28 to 100 bp, preferably from 30 to 50 bp. Preferably, the single strand break or the gap is located at least 6 nucleotides for the extremities of said double-stranded portion, preferably at least 8, 12 or 15 nucleotides. Preferably, the gap is a gap of less than 7 nucleotides, preferably less than 5, more preferably a gap of 1-3 nucleotides, still more preferably a gap of one nucleotide. Preferably, the linker is selected from the group consisting of a polyethyleneglycol chain, an oligonucleotide and any hydrocarbon chain, optionally interrupted and/or substituted by one or more heteroatoms e.g., oxygen, sulfur, or nitrogen, or heteroatomic or heterocyclic groups, comprising one or several heteroatoms. More preferably, it is selected from the group consisting of hexaethyleneglycol, tetradeoxythymidylate (T4) and 2,19-bis(phosphor)-8-hydraza-l-hydroxy-4-oxa-9-oxo-nonadecane.
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