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ONCOGENE TRANSCRIPTION CONTROL REGION

Foreign code F190009780
File No. (S2017-0795-N0)
Posted date May 7, 2019
Country WIPO
International application number 2018JP023028
International publication number WO 2018230731
Date of international filing Jun 15, 2018
Date of international publication Dec 20, 2018
Priority data
  • P2017-119159 (Jun 16, 2017) JP
Title ONCOGENE TRANSCRIPTION CONTROL REGION
Abstract The present invention provides an antitumor agent containing a substance that specifically recognizes a target region of 12 or more consecutive nucleotides including at least part of the Runx binding sequence TGCGGT nearest the transcription initiation site upstream of the transcription initiation site of a c-Myc gene and inhibits the binding of Runx3 to the Runx binding sequence.
Outline of related art and contending technology BACKGROUND ART
Cancer cells are a variety of genetic abnormalities accumulate, over time, been increasing in their complexity. To be opposed thereto, a wide variety of molecular target drugs (anti-cancer agents) are developed, their complexity has not been overcome.
Anti-cancer agents include, the target cell division in addition to the conventional anti-cancer agents, cancer specific variation of the target molecules such as antibodies to the target agent and anti-PD-1, immune to attack cancer immune mechanisms to adjust the immunotherapeutic agent and the like. However, conventional anti-cancer agent is a normal cell is also susceptible to the influence of, the target agent is very effective by the target molecules may be on the other hand, not be very effective, immunotherapy agents, patients undergoing treatment, the effect of problems such as a person is limited.
Accumulate mutations in a cell, in most cases, the mutant is repaired, apoptosis or cell death is due to the attack, and the accumulation of mutations 3-10, and are referred to as cancer. Is one of the mutation, and factors of the common-occurring variant, the molecular basis of a common complex malignant tumor exists. For example, in human cancer, c-Myc and deactivation of the p53 expression of the most widely recognized by an increase. p53 Is the best known are considered to influence the 'tumor suppressor gene' in. Is the primary role of the p53, checks the abnormality in the cell, if there is a problem of inducing apoptosis in. Is p53, 50%-80% of the mutation in all tumor extent (dysfunction, reduction in the amount of expression) are known. In addition, the degree of malignancy, anti-cancer drugs are considered to be correlated with resistance.
p53 For a molecule and its vicinity is very anti-cancer agent in a number of ways are developed, to date have not been successful. Normal p53 is increased and that it is technically difficult and, when the increased amount or more so as to induce apoptosis, normal cells and over-expression will also induce apoptosis (i.e., 'the normal quantity' is difficult to be adjusted). Therefore, the upstream p53, downstream of one or more anti-cancer agent and the target is in development, have not been successful either.
C-Myc is, the proliferation of cells having a role in regulating the protein. C-Myc and knock-down, in preparation for the growth does not occur, the cell cycle is stopped. Apoptosis, proliferation induced at the moment is most likely, the cell cycle and apoptosis is stopped and resistance. Thus, c-Myc also, direct drug discovery target is difficult.
Runx Runt stored in the evolutionary family has a domain, the domain via the coupling to the transcriptional regulatory region of the target gene. Runx family is also, a variety of C-C to interact with a transcription factor (cofactor) and forming a heterodimer, downstream target genes that control the transfer of the group (non-patent document 1) has. Runx1 mammalian Runx family, Runx2 Runx3 and is constructed, these abnormalities can result in a variety of closely related to the disease. For example, the Runx1 of chromosomal translocations in acute myeloid leukemia and a target, by the chromosome instability of the Runx2 (LOH) is the loss of one allele, and the cause of abnormal skull bones are. On the other hand, in the tumor suppressor gene Runx3 of stomach cancer is pointed out that the (non-patent document 2). Further, within the nucleus coupled Runx3 p53, a positive transfer of the target gene group of the p53 control has been suggested (Non-Patent Document 2). In addition, the mouse is knocked down Runx3 is fatal, the mice by half the amount of expression of the life is short, is a function essential to the survival of Runx3 considered, as the target of the anti-cancer agent seems to be unsuitable.
C-Myc transcription of the gene is upstream from the start, a large number of Runx binding sequence is present (ACCACA, TGCGGT), endogenous Runx1 Runx thereof is coupled to the binding sequence, through the interaction of the co-expression of the gene c-Myc be suppressed have been reported (Non-Patent Document 1).
As described above, in many cancers, and p53 c-Myc inactivation of elevated expression of the found common. In addition, a family of Runx, c-Myc and p53 can interact with both the factor has been suggested. However, these factors, the anti-cancer agent is a direct target of drug discovery is considered to be difficult.
Here, human non-small cell lung cancer cell line A549 and cell injection mice NOG, the common recognition sequence Runx1-3 TGTGGT PI polyamide target (Chb-M) was administered, to suppress the proliferation of A549 cells, so as to improve the survival rate has been reported (Non-Patent Document 3). Also, the same document describes that, although not used in the experiments, target TGCGGT piriamido PI (Chb-50) is also disclosed. However, the c-Myc gene to the transcriptional regulatory region, there are a large number of Runx binding sequence, on which part of the recognition sequence are important for Runx is not known. Also, Runx1, Runx2 Runx3 or knock out mice because both embryonic lethal, the target binding sequence number of the above PI Runx piriamido is, a very strong side effects can be expected.
Scope of claims (In Japanese)請求の範囲 [請求項1]
 c-Myc遺伝子の転写開始点の上流における、該転写開始点の最も近傍のRunx結合配列TGCGGTの少なくとも一部を含む、連続する12ヌクレオチド以上の標的領域を特異的に認識し、該Runx結合配列へのRunx3の結合を阻害する物質を含有する、抗腫瘍剤。

[請求項2]
 前記Runx結合配列が、ヒトc-Myc遺伝子の転写開始点から-309~-304番目のヌクレオチド配列、又は他の哺乳動物オルソログにおける該ヌクレオチド配列に対応する配列(counterpart)である、請求項1に記載の剤。

[請求項3]
 p53が不活性化されている対象に適用することを特徴とする、請求項1又は2に記載の剤。

[請求項4]
 前記物質が、前記標的領域内のDNA配列に対するアンチジーンである、請求項1~3のいずれか1項に記載の剤。

[請求項5]
 前記アンチジーンがピロール・イミダゾールポリアミドである、請求項4に記載の剤。

[請求項6]
 前記物質が、前記標的領域に特異的に結合する核酸配列認識モジュールである、請求項1~3のいずれか1項に記載の剤。

[請求項7]
 前記核酸配列認識モジュールが、CRISPR-Cas、ジンクフィンガーモチーフ、TALエフェクター又はPPRモチーフである、請求項6に記載の剤。

[請求項8]
 前記核酸配列認識モジュールがCRISPR-dCasである、請求項6に記載の剤。

[請求項9]
 前記物質が、前記核酸配列認識モジュールと複合体形成するヌクレアーゼとからなる、請求項6又は7に記載の剤。

[請求項10]
 前記物質が、前記ヌクレアーゼで切断される部位で相同組換えを生じさせ得るドナーDNAをさらに含む、請求項9に記載の剤。

[請求項11]
 前記核酸配列認識モジュールが、転写抑制因子と複合体を形成する、請求項6~8のいずれか1項に記載の剤。

[請求項12]
 前記物質が、それをコードする1以上の発現ベクターの形態で提供される、請求項1~3及び6~11のいずれか1項に記載の剤。

[請求項13]
 p53の不活性化を検定するための試薬と組み合わせてなる、請求項1~12のいずれか1項に記載の剤。

[請求項14]
 (1)被検物質の存在下又は非存在下で、c-Myc遺伝子の転写開始点の上流における、該転写開始点の最も近傍のRunx結合配列TGCGGTを含む、連続する12ヌクレオチド以上の部分ヌクレオチド配列を有する二本鎖DNAと、Runx3とを接触させる工程、
(2)該DNAとRunx3との結合を測定する工程、及び
(3)該DNAとRunx3との結合を阻害した被検物質を、抗腫瘍活性を有する物質の候補として選択する工程
を含む、抗腫瘍活性を有する物質のスクリーニング方法。

  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • NAGASAKI UNIVERSITY
  • Inventor
  • ITO, Kosei
IPC(International Patent Classification)
Specified countries National States: AE AG AL AM AO AT AU AZ BA BB BG BH BN BR BW BY BZ CA CH CL CN CO CR CU CZ DE DJ DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IR IS JO JP KE KG KH KN KP KR KW KZ LA LC LK LR LS LU LY MA MD ME 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 SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW KM ML MR NE SN ST TD TG
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