JPWO2019169219A5 - - Google Patents

Download PDF

Info

Publication number
JPWO2019169219A5
JPWO2019169219A5 JP2020545734A JP2020545734A JPWO2019169219A5 JP WO2019169219 A5 JPWO2019169219 A5 JP WO2019169219A5 JP 2020545734 A JP2020545734 A JP 2020545734A JP 2020545734 A JP2020545734 A JP 2020545734A JP WO2019169219 A5 JPWO2019169219 A5 JP WO2019169219A5
Authority
JP
Japan
Prior art keywords
nucleoside
compound
wing segment
salt
modified oligonucleotide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
JP2020545734A
Other languages
Japanese (ja)
Other versions
JP2021514657A (en
JP7239597B2 (en
Publication date
Application filed filed Critical
Priority claimed from PCT/US2019/020201 external-priority patent/WO2019169219A1/en
Publication of JP2021514657A publication Critical patent/JP2021514657A/en
Publication of JPWO2019169219A5 publication Critical patent/JPWO2019169219A5/ja
Priority to JP2023031616A priority Critical patent/JP2023071856A/en
Application granted granted Critical
Publication of JP7239597B2 publication Critical patent/JP7239597B2/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Description

Figure 2019169219000004
ある態様において、本発明は以下であってもよい。
［態様１］配列番号３～３３８３の核酸塩基配列のうちのいずれかの少なくとも８個の隣接する核酸塩基を含む核酸塩基配列を有する８～８０結合ヌクレオシド長の修飾されたオリゴヌクレオチドを含む化合物。
［態様２］配列番号３～３３８３の核酸塩基配列のうちのいずれかの少なくとも９個の隣接する核酸塩基を含む核酸塩基配列を有する９～８０結合ヌクレオシド長の修飾されたオリゴヌクレオチドを含む化合物。
［態様３］配列番号３～３３８３の核酸塩基配列のうちのいずれかの少なくとも１０個の隣接する核酸塩基を含む核酸塩基配列を有する１０～８０結合ヌクレオシド長の修飾されたオリゴヌクレオチドを含む化合物。
［態様４］配列番号３～３３８３の核酸塩基配列のうちのいずれかの少なくとも１１個の隣接する核酸塩基を含む核酸塩基配列を有する１１～８０結合ヌクレオシド長の修飾されたオリゴヌクレオチドを含む化合物。
［態様５］配列番号３～３３８３の核酸塩基配列のうちのいずれかの少なくとも１２個の隣接する核酸塩基を含む核酸塩基配列を有する１２～８０結合ヌクレオシド長の修飾されたオリゴヌクレオチドを含む化合物。
［態様６］配列番号３～３３８３のうちのいずれか１つの核酸塩基配列を含む核酸塩基配列を有する１６～８０結合ヌクレオシド長の修飾されたオリゴヌクレオチドを含む化合物。
［態様７］配列番号３～３３８３のうちのいずれか１つからなる核酸塩基配列を有する修飾されたオリゴヌクレオチドを含む化合物。
［態様８］配列番号１のヌクレオチド４２２７～４２４４、４２２７～４２４２、４２２８～４２４３、もしくは４２２９～４２４４内または配列番号２のヌクレオチド９６６７～９６８２、１１４１１～１１４２６、もしくは１８０９０～１８１０５内で相補的な８～８０結合ヌクレオシド長の修飾されたオリゴヌクレオチドを含む化合物。
［態様９］配列番号２０２１、５６０、５５９、１３３０、１５４０、または３３０３のうちのいずれか１つを含む核酸塩基配列を有する８～８０結合ヌクレオシド長の修飾されたオリゴヌクレオチドを含む化合物。
［態様１０］配列番号２０２１、５６０、５５９、１３３０、１５４０、または３３０３のうちのいずれか１つからなる核酸塩基配列を有する修飾されたオリゴヌクレオチドを含む化合物。
［態様１１］前記修飾されたオリゴヌクレオチドが、少なくとも１つの修飾されたヌクレオシド間結合、少なくとも１つの修飾された糖、または少なくとも１つの修飾された核酸塩基を含む、態様１～１０のいずれか１に記載の化合物。
［態様１２］前記修飾されたヌクレオシド間結合が、ホスホロチオエートヌクレオシド間結合である、態様１１に記載の化合物。
［態様１３］前記修飾された糖が、二環式糖である、態様１１または１２に記載の化合物。
［態様１４］前記二環式糖が、４’－（ＣＨ２）－Ｏ－２’（ＬＮＡ）、４’－（ＣＨ２）２－Ｏ－２’（ＥＮＡ）、及び４’－ＣＨ（ＣＨ３）－Ｏ－２’（ｃＥｔ）からなる群から選択される、態様１３に記載の化合物。
［態様１５］前記修飾された糖が、２’－Ｏ－メトキシエチルである、態様１１または１２に記載の化合物。
［態様１６］前記修飾された核酸塩基が、５－メチルシトシンである、態様１１～１５のいずれか１に記載の化合物。
［態様１７］前記修飾されたオリゴヌクレオチドが、
結合されたデオキシヌクレオシドからなるギャップセグメントと、
結合されたヌクレオシドからなる５’ウイングセグメントと、
結合されたヌクレオシドからなる３’ウイングセグメントと、を含み、
前記ギャップセグメントが、前記５’ウイングセグメントと前記３’ウイングセグメントとの間に配置され、各ウイングセグメントの各ヌクレオシドが、修飾された糖を含む、態様１～１６のいずれか１に記載の化合物。
［態様１８］配列番号２０２１、５６０、５５９、１３３０、１５４０、または３３０３のうちのいずれか１つを含む核酸塩基配列を有する１６～８０結合ヌクレオシド長の修飾されたオリゴヌクレオチドを含む化合物であって、前記修飾されたオリゴヌクレオチドが、
結合されたデオキシヌクレオシドからなるギャップセグメントと、
結合されたヌクレオシドからなる５’ウイングセグメントと、
結合されたヌクレオシドからなる３’ウイングセグメントと、を含み、
前記ギャップセグメントが、前記５’ウイングセグメントと前記３’ウイングセグメントとの間に配置され、各ウイングセグメントの各ヌクレオシドが、修飾された糖を含む、前記化合物。
［態様１９］配列番号１３３０または３３０３のうちのいずれか１つに列挙される配列を含む核酸塩基配列を有する１６～８０結合核酸塩基長の修飾されたオリゴヌクレオチドを含む化合物であって、前記修飾されたオリゴヌクレオチドが、
１０個の結合されたデオキシヌクレオシドからなるギャップセグメントと、
３個の結合されたヌクレオシドからなる５’ウイングセグメントと、
３個の結合されたヌクレオシドからなる３’ウイングセグメントと、を含み、
前記ギャップセグメントが、前記５’ウイングセグメントと前記３’ウイングセグメントとの間に配置され、各ウイングセグメントの各ヌクレオシドが、ｃＥｔヌクレオシドを含み、各ヌクレオシド間結合が、ホスホロチオエート結合であり、各シトシンが、５－メチルシトシンである、前記化合物。
［態様２０］配列番号５５９または５６０のうちのいずれか１つに列挙される配列を含む核酸塩基配列を有する１６～８０結合核酸塩基長の修飾されたオリゴヌクレオチドを含む化合物であって、前記修飾されたオリゴヌクレオチドが、
１０個の結合されたデオキシヌクレオシドからなるギャップセグメントと、
１個の結合されたヌクレオシドからなる５’ウイングセグメントと、
５個の結合されたヌクレオシドからなる３’ウイングセグメントと、を含み、
前記ギャップセグメントが、前記５’ウイングセグメントと前記３’ウイングセグメントとの間に配置され、前記５’ウイングセグメントが、ｃＥｔヌクレオシドを含み、前記３’ウイングセグメントが、５’～３’の方向で、ｃＥｔヌクレオシド、２’－Ｏ－メトキシエチルヌクレオシド、ｃＥｔヌクレオシド、２’－Ｏ－メトキシエチルヌクレオシド、及びｃＥｔヌクレオシドを含み、各ヌクレオシド間結合が、ホスホロチオエート結合であり、各シトシンが、５－メチルシトシンである、前記化合物。
［態様２１］配列番号１３３０または２０２１のうちのいずれか１つに列挙される配列を含む核酸塩基配列を有する１６～８０結合核酸塩基長の修飾されたオリゴヌクレオチドを含む化合物であって、前記修飾されたオリゴヌクレオチドが、
１０個の結合されたデオキシヌクレオシドからなるギャップセグメントと、
２個の結合されたヌクレオシドからなる５’ウイングセグメントと、
４個の結合されたヌクレオシドからなる３’ウイングセグメントと、を含み、
前記ギャップセグメントが、前記５’ウイングセグメントと前記３’ウイングセグメントとの間に配置され、前記５’ウイングセグメントの各ヌクレオシドが、ｃＥｔヌクレオシドを含み、前記３’ウイングセグメントが、５’～３’の方向で、ｃＥｔヌクレオシド、２’－Ｏ－メトキシエチルヌクレオシド、ｃＥｔヌクレオシド、及び２’－Ｏ－メトキシエチルヌクレオシドを含み、各ヌクレオシド間結合が、ホスホロチオエート結合であり、各シトシンが、５－メチルシトシンである、前記化合物。
［態様２２］配列番号５６０に列挙される配列を含む核酸塩基配列を有する１６～８０結合核酸塩基長の修飾されたオリゴヌクレオチドを含む化合物であって、前記修飾されたオリゴヌクレオチドが、
９個の結合されたデオキシヌクレオシドからなるギャップセグメントと、
２個の結合されたヌクレオシドからなる５’ウイングセグメントと、
５個の結合されたヌクレオシドからなる３’ウイングセグメントと、を含み、
前記ギャップセグメントが、前記５’ウイングセグメントと前記３’ウイングセグメントとの間に配置され、前記５’ウイングセグメントの各ヌクレオシドが、ｃＥｔヌクレオシドを含み、前記３’ウイングセグメントが、５’～３’の方向で、ｃＥｔヌクレオシド、２’－Ｏ－メトキシエチルヌクレオシド、ｃＥｔヌクレオシド、２’－Ｏ－メトキシエチルヌクレオシド、及びｃＥｔヌクレオシドを含み、各ヌクレオシド間結合が、ホスホロチオエート結合であり、各シトシンが、５－メチルシトシンである、前記化合物。
［態様２３］配列番号２０２１に列挙される配列を含む核酸塩基配列を有する１６～８０結合核酸塩基長の修飾されたオリゴヌクレオチドを含む化合物であって、前記修飾されたオリゴヌクレオチドが、
９個の結合されたデオキシヌクレオシドからなるギャップセグメントと、
２個の結合されたヌクレオシドからなる５’ウイングセグメントと、
５個の結合されたヌクレオシドからなる３’ウイングセグメントと、を含み、
前記ギャップセグメントが、前記５’ウイングセグメントと前記３’ウイングセグメントとの間に配置され、前記５’ウイングセグメントの各ヌクレオシドが、ｃＥｔヌクレオシドを含み、前記３’ウイングセグメントが、５’～３’の方向で、２’－Ｏ－メトキシエチルヌクレオシド、２’－Ｏ－メトキシエチルヌクレオシド、２’－Ｏ－メトキシエチルヌクレオシド、ｃＥｔヌクレオシド、及びｃＥｔヌクレオシドを含み、各ヌクレオシド間結合が、ホスホロチオエート結合であり、各シトシンが、５－メチルシトシンである、前記化合物。
［態様２４］配列番号１５４０に列挙される配列を含む核酸塩基配列を有する１６～８０結合核酸塩基長の修飾されたオリゴヌクレオチドを含む化合物であって、前記修飾されたオリゴヌクレオチドが、
９個の結合されたデオキシヌクレオシドからなるギャップセグメントと、
２個の結合されたヌクレオシドからなる５’ウイングセグメントと、
５個の結合されたヌクレオシドからなる３’ウイングセグメントと、を含み、
前記ギャップセグメントが、前記５’ウイングセグメントと前記３’ウイングセグメントとの間に配置され、前記５’ウイングセグメントの各ヌクレオシドが、ｃＥｔヌクレオシドを含み、前記３’ウイングセグメントが、５’～３’の方向で、２’－Ｏ－メトキシエチルヌクレオシド、２’－Ｏ－メトキシエチルヌクレオシド、２’－Ｏ－メトキシエチルヌクレオシド、ｃＥｔヌクレオシド、及びｃＥｔヌクレオシドを含み、各ヌクレオシド間結合が、ホスホロチオエート結合であり、各シトシンが、５－メチルシトシンである、前記化合物。
［態様２５］配列番号５６０に列挙される配列を含む核酸塩基配列を有する１６～８０結合核酸塩基長の修飾されたオリゴヌクレオチドを含む化合物であって、前記修飾されたオリゴヌクレオチドが、
９個の結合されたデオキシヌクレオシドからなるギャップセグメントと、
２個の結合されたヌクレオシドからなる５’ウイングセグメントと、
５個の結合されたヌクレオシドからなる３’ウイングセグメントと、を含み、
前記ギャップセグメントが、前記５’ウイングセグメントと前記３’ウイングセグメントとの間に配置され、前記５’ウイングセグメントの各ヌクレオシドが、ｃＥｔヌクレオシドを含み、前記３’ウイングセグメントが、５’～３’の方向で、２’－Ｏ－メトキシエチルヌクレオシド、ｃＥｔヌクレオシド、２’－Ｏ－メトキシエチルヌクレオシド、ｃＥｔヌクレオシド、及び２’－Ｏ－メトキシエチルヌクレオシドを含み、各ヌクレオシド間結合が、ホスホロチオエート結合であり、各シトシンが、５－メチルシトシンである、前記化合物。
［態様２６］前記オリゴヌクレオチドが、配列番号１または２と少なくとも８０％、８５％、９０％、９５％、または１００％相補的である、態様１～２５のいずれか１に記載の化合物。
［態様２７］前記化合物が、一本鎖である、態様１～２６のいずれか１に記載の化合物。
［態様２８］前記化合物が、二本鎖である、態様１～２６のいずれか１に記載の化合物。
［態様２９］前記化合物が、リボヌクレオチドを含む、態様１～２８のいずれか１に記載の化合物。
［態様３０］前記化合物が、デオキシリボヌクレオチドを含む、態様１～２８のいずれか１に記載の化合物。
［態様３１］前記修飾されたオリゴヌクレオチドが、１６～３０個の結合されたヌクレオシドからなる、態様１～３０のいずれか１に記載の化合物。
［態様３２］前記化合物が、前記修飾されたオリゴヌクレオチドからなる、先行態様のいずれかに記載の化合物。
［態様３３］態様１～３２に記載の化合物のうちのいずれかの薬学的に許容される塩からなる化合物。
［態様３４］前記薬学的に許容される塩が、ナトリウム塩である、態様３３に記載の化合物。
［態様３５］前記薬学的に許容される塩が、カリウム塩である、態様３３に記載の化合物。
［態様３６］以下の式を有する化合物、
Figure 2019169219000005
 またはその塩。
［態様３７］以下の式を有する化合物。
Figure 2019169219000006
 ［態様３８］以下の式を有する化合物、
Figure 2019169219000007
 またはその塩。
［態様３９］以下の式を有する化合物。
Figure 2019169219000008
 ［態様４０］態様１～３９のいずれか１に記載の化合物及び薬学的に許容される担体を含む組成物。
［態様４１］治療に使用するための、先行態様のいずれかに記載の化合物または修飾されたオリゴヌクレオチドを含む組成物。
［態様４２］個体におけるがんを治療または改善する方法であって、ＩＲＦ４を標的とする化合物を前記個体に投与し、それにより前記がんを治療または改善することを含む、前記方法。
［態様４３］前記化合物が、ＩＲＦ４を標的とするアンチセンス化合物である、態様４２に記載の方法。
［態様４４］前記がんが、血液がん、骨髄腫、多発性骨髄腫（ＭＭ）、Ｂ細胞悪性腫瘍、リンパ腫、Ｂ細胞リンパ腫、Ｔ細胞リンパ腫、または白血病である、態様４２または４３に記載の方法。
［態様４５］前記化合物を投与することが、がん細胞増殖、腫瘍増殖、または転移を阻害または低減する、態様４２～４４のいずれかに記載の方法。
［態様４６］細胞内のＩＲＦ４の発現を阻害する方法であって、前記細胞を、ＩＲＦ４を標的とする化合物と接触させて、それにより前記細胞内のＩＲＦ４の発現を阻害することを含む、前記方法。
［態様４７］前記細胞が、がん細胞である、態様４８に記載の方法。
［態様４８］前記個体が、血液がん、骨髄腫、多発性骨髄腫（ＭＭ）、Ｂ細胞悪性腫瘍、リンパ腫、Ｂ細胞リンパ腫、Ｔ細胞リンパ腫、または白血病を有する、態様４７に記載の方法。
［態様４９］がんを有する個体におけるがん細胞増殖、腫瘍増殖、または転移を低減または阻害する方法であって、ＩＲＦ４を標的とする化合物を前記個体に投与し、それにより前記個体におけるがん細胞増殖、腫瘍増殖、または転移を低減または阻害することを含む、前記方法。
［態様５０］前記個体が、血液がん、骨髄腫、多発性骨髄腫（ＭＭ）、Ｂ細胞悪性腫瘍、リンパ腫、Ｂ細胞リンパ腫、Ｔ細胞リンパ腫、または白血病を有する、態様４９に記載の方法。
［態様５１］前記化合物が、ＩＲＦ４を標的とするアンチセンス化合物である、態様４６～５０のいずれか１に記載の方法。
［態様５２］前記化合物が、態様１～３９のいずれか１に記載の化合物または態様４０もしくは４１に記載の組成物である、態様４６～５１のいずれか１に記載の方法。
［態様５３］前記化合物が、非経口的に投与される、態様４２～５２のいずれかに記載の方法。
［態様５４］ＩＲＦ４に関連するがんを治療、予防、または改善するための、ＩＲＦ４を標的とする化合物の使用。
［態様５５］前記がんが、血液がん、骨髄腫、多発性骨髄腫（ＭＭ）、Ｂ細胞悪性腫瘍、リンパ腫、Ｂ細胞リンパ腫、Ｔ細胞リンパ腫、または白血病である、態様５４に記載の使用。
［態様５６］前記化合物が、ＩＲＦ４を標的とするアンチセンス化合物である、態様５４または５５に記載の使用。
［態様５７］前記化合物が、態様１～３９のいずれか１に記載の化合物または態様４０もしくは４１に記載の組成物である、態様５４～５６のいずれか１に記載の使用。
［態様５８］ＩＲＦ４に関連するがんを治療または改善するための、医薬品の製造におけるＩＲＦ４を標的とする化合物の使用。
［態様５９］前記がんが、血液がん、骨髄腫、多発性骨髄腫（ＭＭ）、Ｂ細胞悪性腫瘍、リンパ腫、Ｂ細胞リンパ腫、Ｔ細胞リンパ腫、または白血病である、態様５８に記載の使用。
［態様６０］前記化合物が、ＩＲＦ４を標的とするアンチセンス化合物である、態様５８または５９に記載の使用。
［態様６１］前記化合物が、態様１～３９のいずれか１に記載の化合物または態様４０もしくは４１に記載の組成物である、態様５８～６０のいずれか１に記載の使用。
［態様６２］ＩＲＦ４に関連するがんを治療または改善するための、医薬品の調製におけるＩＲＦ４を標的とする化合物の使用。
［態様６３］前記がんが、血液がん、骨髄腫、多発性骨髄腫（ＭＭ）、Ｂ細胞悪性腫瘍、リンパ腫、Ｂ細胞リンパ腫、Ｔ細胞リンパ腫、または白血病である、態様６２に記載の使用。
［態様６４］前記化合物が、ＩＲＦ４を標的とするアンチセンス化合物である、態様６２または６３に記載の使用。
［態様６５］前記化合物が、態様１～３９のいずれか１に記載の化合物または態様４０もしくは４１に記載の組成物である、態様６２～６４のいずれか１に記載の使用。
Figure 2019169219000004
In some embodiments, the invention may be:
[Aspect 1] A compound containing a modified oligonucleotide having an 8 to 80-binding nucleoside length having a nucleobase sequence containing at least 8 adjacent nucleobases from any of the nucleobase sequences of SEQ ID NOs: 3 to 3383.
[Aspect 2] A compound containing a modified oligonucleotide having a 9-80 binding nucleoside length having a nucleobase sequence containing at least 9 adjacent nucleobases of any of the nucleobase sequences of SEQ ID NOs: 3 to 3383.
[Aspect 3] A compound comprising a modified oligonucleotide having a 10-80 binding nucleoside length having a nucleobase sequence containing at least 10 adjacent nucleobases of any of the nucleobase sequences of SEQ ID NOs: 3 to 3383.
[Aspect 4] A compound comprising a modified oligonucleotide having an 11-80 binding nucleoside length having a nucleobase sequence containing at least 11 adjacent nucleobases of any of the nucleobase sequences of SEQ ID NOs: 3 to 3383.
[Aspect 5] A compound comprising a modified oligonucleotide having a 12-80 binding nucleoside length having a nucleobase sequence containing at least 12 adjacent nucleobases of any of the nucleobase sequences of SEQ ID NOs: 3 to 3383.
[Aspect 6] A compound comprising a modified oligonucleotide having a 16-80 binding nucleoside length having a nucleic acid base sequence containing any one of SEQ ID NOs: 3 to 3383.
[Aspect 7] A compound containing a modified oligonucleotide having a nucleobase sequence consisting of any one of SEQ ID NOs: 3 to 3383.
[Aspect 8] Complementary 8 within nucleotides 4227 to 4244, 4227 to 4242, 4228 to 4243, or 4229 to 4244 of SEQ ID NO: 1 or nucleotides 9667 to 9682, 11411 to 11426, or 18090 to 18105 of SEQ ID NO: 2. A compound containing a modified oligonucleotide having a nucleoside length of -80 binding.
[Aspect 9] A compound comprising a modified oligonucleotide having an 8-80 binding nucleoside length having a nucleobase sequence comprising any one of SEQ ID NOs: 2021, 560, 559, 1330, 1540, or 3303.
[Aspect 10] A compound comprising a modified oligonucleotide having a nucleobase sequence consisting of any one of SEQ ID NOs: 2021, 560, 559, 1330, 1540, or 3303.
[Aspect 11] Any one of aspects 1-10, wherein the modified oligonucleotide comprises at least one modified nucleoside bond, at least one modified sugar, or at least one modified nucleobase. The compound described in.
[Aspect 12] The compound according to aspect 11, wherein the modified nucleoside bond is a phosphorothioate nucleoside bond.
[Aspect 13] The compound according to aspect 11 or 12, wherein the modified sugar is a bicyclic sugar.
[Aspect 14] The bicyclic sugar is 4'-(CH 2 ) -O-2'(LNA), 4'-(CH 2 ) 2 -O-2'(ENA), and 4'-CH ( The compound according to embodiment 13, selected from the group consisting of CH 3 ) -O-2'(cEt).
[Aspect 15] The compound according to aspect 11 or 12, wherein the modified sugar is 2'-O-methoxyethyl.
[Aspect 16] The compound according to any one of aspects 11 to 15, wherein the modified nucleobase is 5-methylcytosine.
[Aspect 17] The modified oligonucleotide is
A gap segment consisting of bound deoxynucleosides,
A 5'wing segment consisting of bound nucleosides and
Includes a 3'wing segment consisting of bound nucleosides,
The compound according to any one of aspects 1 to 16, wherein the gap segment is located between the 5'wing segment and the 3'wing segment, and each nucleoside in each wing segment comprises a modified sugar. ..
[Aspect 18] A compound comprising a modified oligonucleotide having a 16-80 binding nucleoside length having a nucleobase sequence comprising any one of SEQ ID NOs: 2021, 560, 559, 1330, 1540, or 3303. , The modified oligonucleotide
A gap segment consisting of bound deoxynucleosides,
A 5'wing segment consisting of bound nucleosides and
Includes a 3'wing segment consisting of bound nucleosides,
The compound, wherein the gap segment is located between the 5'wing segment and the 3'wing segment, and each nucleoside in each wing segment comprises a modified sugar.
[Aspect 19] A compound comprising a modified oligonucleotide having a 16-80 binding nucleic acid base length having a nucleic acid base sequence containing a sequence listed in any one of SEQ ID NO: 1330 or 3303, wherein the modification is made. The oligonucleotide is
A gap segment consisting of 10 bound deoxynucleosides,
A 5'wing segment consisting of three combined nucleosides,
Includes a 3'wing segment consisting of 3 bound nucleosides,
The gap segment is located between the 5'wing segment and the 3'wing segment, each nucleoside in each wing segment comprises a cEt nucleoside, each nucleoside bond is a phosphorothioate bond, and each cytosine. , 5-Methylcytosine, said compound.
[Aspect 20] A compound comprising a modified oligonucleotide having a 16-80 binding nucleic acid base length having a nucleic acid base sequence containing a sequence listed in any one of SEQ ID NO: 559 or 560, wherein the modification is made. The oligonucleotide is
A gap segment consisting of 10 bound deoxynucleosides,
A 5'wing segment consisting of one bound nucleoside,
Includes a 3'wing segment consisting of 5 combined nucleosides,
The gap segment is located between the 5'wing segment and the 3'wing segment, the 5'wing segment contains a cEt nucleoside, and the 3'wing segment is in the 5'-3'direction. , CEt nucleosides, 2'-O-methoxyethyl nucleosides, cEt nucleosides, 2'-O-methoxyethyl nucleosides, and cEt nucleosides, where each nucleoside bond is a phosphorothioate bond and each cytosine is 5-methylcytosine. The compound.
[Aspect 21] A compound comprising a modified oligonucleotide having a nucleobase sequence of 16 to 80 binding having a nucleobase sequence including a sequence listed in any one of SEQ ID NO: 1330 or 2021 and having the above-mentioned modification. The oligonucleotide is
A gap segment consisting of 10 bound deoxynucleosides,
A 5'wing segment consisting of two combined nucleosides,
Includes a 3'wing segment consisting of 4 combined nucleosides,
The gap segment is located between the 5'wing segment and the 3'wing segment, each nucleoside of the 5'wing segment contains a cEt nucleoside, and the 3'wing segment is 5'-3'. In the direction of, it comprises a cEt nucleoside, 2'-O-methoxyethyl nucleoside, cEt nucleoside, and 2'-O-methoxyethyl nucleoside, where each nucleoside bond is a phosphorothioate bond and each cytosine is 5-methylcytosine. The compound.
[Aspect 22] A compound comprising a modified oligonucleotide having a nucleic acid base sequence having a nucleic acid base sequence including the sequence listed in SEQ ID NO: 560 and having a nucleobase length of 16 to 80, wherein the modified oligonucleotide is:
A gap segment consisting of 9 bound deoxynucleosides,
A 5'wing segment consisting of two combined nucleosides,
Includes a 3'wing segment consisting of 5 combined nucleosides,
The gap segment is located between the 5'wing segment and the 3'wing segment, each nucleoside of the 5'wing segment contains a cEt nucleoside, and the 3'wing segment is 5'-3'. Includes cEt nucleosides, 2'-O-methoxyethyl nucleosides, cEt nucleosides, 2'-O-methoxyethyl nucleosides, and cEt nucleosides, where each nucleoside bond is a phosphorothioate bond and each cytosine is 5. -The compound, which is methylcytosine.
[Aspect 23] A compound comprising a modified oligonucleotide having a nucleic acid base sequence having a nucleic acid base sequence including the sequence listed in SEQ ID NO: 2021 and having a nucleobase length of 16 to 80, wherein the modified oligonucleotide is:
A gap segment consisting of 9 bound deoxynucleosides,
A 5'wing segment consisting of two combined nucleosides,
Includes a 3'wing segment consisting of 5 combined nucleosides,
The gap segment is located between the 5'wing segment and the 3'wing segment, each nucleoside of the 5'wing segment contains a cEt nucleoside, and the 3'wing segment is 5'-3'. In the direction of 2'-O-methoxyethyl nucleoside, 2'-O-methoxyethyl nucleoside, 2'-O-methoxyethyl nucleoside, cEt nucleoside, and cEt nucleoside, each nucleoside bond is a phosphorothioate bond. , Each cytosine is 5-methylcytosine, said compound.
[Aspect 24] A compound comprising a modified oligonucleotide having a nucleic acid base sequence having a nucleic acid base sequence including the sequence listed in SEQ ID NO: 1540 and having a nucleobase length of 16 to 80, wherein the modified oligonucleotide is:
A gap segment consisting of 9 bound deoxynucleosides,
A 5'wing segment consisting of two combined nucleosides,
Includes a 3'wing segment consisting of 5 combined nucleosides,
The gap segment is located between the 5'wing segment and the 3'wing segment, each nucleoside of the 5'wing segment contains a cEt nucleoside, and the 3'wing segment is 5'-3'. In the direction of 2'-O-methoxyethyl nucleoside, 2'-O-methoxyethyl nucleoside, 2'-O-methoxyethyl nucleoside, cEt nucleoside, and cEt nucleoside, each nucleoside bond is a phosphorothioate bond. , Each cytosine is 5-methylcytosine, said compound.
[Aspect 25] A compound comprising a modified oligonucleotide having a nucleic acid base sequence having a nucleic acid base sequence including the sequence listed in SEQ ID NO: 560 and having a nucleobase length of 16 to 80, wherein the modified oligonucleotide is:
A gap segment consisting of 9 bound deoxynucleosides,
A 5'wing segment consisting of two combined nucleosides,
Includes a 3'wing segment consisting of 5 combined nucleosides,
The gap segment is located between the 5'wing segment and the 3'wing segment, each nucleoside of the 5'wing segment contains a cEt nucleoside, and the 3'wing segment is 5'-3'. In the direction of 2'-O-methoxyethyl nucleoside, cEt nucleoside, 2'-O-methoxyethyl nucleoside, cEt nucleoside, and 2'-O-methoxyethyl nucleoside, each nucleoside bond is a phosphorothioate bond. , Each cytosine is 5-methylcytosine, said compound.
[Aspect 26] The compound according to any one of aspects 1 to 25, wherein the oligonucleotide is at least 80%, 85%, 90%, 95%, or 100% complementary to SEQ ID NO: 1 or 2.
[Aspect 27] The compound according to any one of aspects 1 to 26, wherein the compound is a single chain.
[Aspect 28] The compound according to any one of aspects 1 to 26, wherein the compound is double-stranded.
[Aspect 29] The compound according to any one of aspects 1 to 28, wherein the compound comprises a ribonucleotide.
[Aspect 30] The compound according to any one of aspects 1 to 28, wherein the compound comprises a deoxyribonucleotide.
[Aspect 31] The compound according to any one of aspects 1 to 30, wherein the modified oligonucleotide consists of 16 to 30 bound nucleosides.
[Aspect 32] The compound according to any of the preceding embodiments, wherein the compound comprises the modified oligonucleotide.
[Aspect 33] A compound consisting of a pharmaceutically acceptable salt of any of the compounds according to Aspects 1 to 32.
[Aspect 34] The compound according to Aspect 33, wherein the pharmaceutically acceptable salt is a sodium salt.
[Aspect 35] The compound according to Aspect 33, wherein the pharmaceutically acceptable salt is a potassium salt.
[Aspect 36] A compound having the following formula,
Figure 2019169219000005
 Or its salt.
[Aspect 37] A compound having the following formula.
Figure 2019169219000006
 [Aspect 38] A compound having the following formula,
Figure 2019169219000007
 Or its salt.
[Aspect 39] A compound having the following formula.
Figure 2019169219000008
 [Aspect 40] A composition comprising the compound according to any one of aspects 1 to 39 and a pharmaceutically acceptable carrier.
[Aspect 41] A composition comprising the compound or modified oligonucleotide according to any of the preceding embodiments for use in therapy.
42. A method of treating or ameliorating cancer in an individual, comprising administering to the individual a compound targeting IRF4, thereby treating or ameliorating the cancer.
[Aspect 43] The method of aspect 42, wherein the compound is an antisense compound that targets IRF4.
[Aspect 44] The aspect 42 or 43, wherein the cancer is a hematological cancer, myeloma, multiple myeloma (MM), B-cell malignant tumor, lymphoma, B-cell lymphoma, T-cell lymphoma, or leukemia. the method of.
[Aspect 45] The method of any of aspects 42-44, wherein administering the compound inhibits or reduces cancer cell growth, tumor growth, or metastasis.
[Aspect 46] A method for inhibiting the expression of IRF4 in a cell, which comprises contacting the cell with a compound targeting IRF4, thereby inhibiting the expression of IRF4 in the cell. Method.
[Aspect 47] The method according to aspect 48, wherein the cell is a cancer cell.
48. The method of aspect 47, wherein the individual has hematological carcinoma, myeloma, multiple myeloma (MM), B-cell malignant tumor, lymphoma, B-cell lymphoma, T-cell lymphoma, or leukemia.
[Aspect 49] A method for reducing or inhibiting cancer cell growth, tumor growth, or metastasis in an individual having cancer, wherein a compound targeting IRF4 is administered to the individual, thereby causing cancer in the individual. The method described above comprising reducing or inhibiting cell growth, tumor growth, or metastasis.
50. The method of aspect 49, wherein the individual has hematological carcinoma, myeloma, multiple myeloma (MM), B-cell malignant tumor, lymphoma, B-cell lymphoma, T-cell lymphoma, or leukemia.
[Aspect 51] The method according to any one of aspects 46-50, wherein the compound is an antisense compound that targets IRF4.
[Aspect 52] The method according to any one of aspects 46 to 51, wherein the compound is the compound according to any one of aspects 1 to 39 or the composition according to aspects 40 or 41.
[Aspect 53] The method according to any of aspects 42-52, wherein the compound is administered parenterally.
[Aspect 54] Use of a compound that targets IRF4 to treat, prevent, or ameliorate cancer associated with IRF4.
[Aspect 55] The use according to aspect 54, wherein the cancer is a hematological cancer, myeloma, multiple myeloma (MM), B-cell malignant tumor, lymphoma, B-cell lymphoma, T-cell lymphoma, or leukemia. ..
[Aspect 56] The use according to aspect 54 or 55, wherein the compound is an antisense compound that targets IRF4.
[Aspect 57] The use according to any one of aspects 54 to 56, wherein the compound is the compound according to any one of aspects 1 to 39 or the composition according to aspects 40 or 41.
[Aspect 58] Use of a compound targeting IRF4 in the manufacture of a pharmaceutical product to treat or ameliorate a cancer associated with IRF4.
[Aspect 59] The use according to aspect 58, wherein the cancer is a hematological cancer, myeloma, multiple myeloma (MM), B-cell malignant tumor, lymphoma, B-cell lymphoma, T-cell lymphoma, or leukemia. ..
[Aspect 60] The use according to aspect 58 or 59, wherein the compound is an antisense compound that targets IRF4.
[Aspect 61] The use according to any one of aspects 58 to 60, wherein the compound is the compound according to any one of aspects 1 to 39 or the composition according to aspects 40 or 41.
[Aspect 62] Use of a compound targeting IRF4 in the preparation of a pharmaceutical product to treat or ameliorate a cancer associated with IRF4.
[Aspect 63] The use according to aspect 62, wherein the cancer is a hematological cancer, myeloma, multiple myeloma (MM), B-cell malignant tumor, lymphoma, B-cell lymphoma, T-cell lymphoma, or leukemia. ..
[Aspect 64] The use according to aspect 62 or 63, wherein the compound is an antisense compound that targets IRF4.
[Aspect 65] The use according to any one of aspects 62 to 64, wherein the compound is the compound according to any one of aspects 1 to 39 or the composition according to aspects 40 or 41.

Claims (14)

１６個の結合された核酸塩基からなり、配列番号２０２１の核酸塩基配列からなる核酸塩基配列を有する修飾されたオリゴヌクレオチドを含む、オリゴマー化合物又はその塩であって、該修飾されたオリゴヌクレオチドが、
９個の結合されたデオキシヌクレオシドからなるギャップセグメントと、
２個の結合されたヌクレオシドからなる５’ウイングセグメントと、
５個の結合されたヌクレオシドからなる３’ウイングセグメントと、を含み、
該ギャップセグメントが、該５’ウイングセグメントと該３’ウイングセグメントとの間に配置され、該５’ウイングセグメントの各ヌクレオシドが、ｃＥｔヌクレオシドを含み、該３’ウイングセグメントが、５’から３’の方向で、２’－Ｏ－メトキシエチルヌクレオシド、２’－Ｏ－メトキシエチルヌクレオシド、２’－Ｏ－メトキシエチルヌクレオシド、ｃＥｔヌクレオシド、及びｃＥｔヌクレオシドを含み、各ヌクレオシド間結合が、ホスホロチオエート結合であり、各シトシンが、５－メチルシトシンである、上記化合物又はその塩。 An oligomer compound or a salt thereof comprising a modified oligonucleotide consisting of 16 linked nucleobases and having a nucleobase sequence consisting of the nucleobase sequence of SEQ ID NO: 2021, wherein the modified oligonucleotide is:
A gap segment consisting of 9 bound deoxynucleosides,
A 5'wing segment consisting of two combined nucleosides,
Includes a 3'wing segment consisting of 5 combined nucleosides,
The gap segment is located between the 5'wing segment and the 3'wing segment, each nucleoside of the 5'wing segment contains a cEt nucleoside, and the 3'wing segment is 5'to 3'. In the direction of 2'-O-methoxyethyl nucleoside, 2'-O-methoxyethyl nucleoside, 2'-O-methoxyethyl nucleoside, cEt nucleoside, and cEt nucleoside, each nucleoside bond is a phosphorothioate bond. , Each cytosine is 5-methylcytosine, the above compound or a salt thereof. 塩がナトリウム塩又はカリウム塩である、請求項１に記載のオリゴマー化合物又はその塩。 The oligomer compound or salt thereof according to claim 1, wherein the salt is a sodium salt or a potassium salt. 以下の化学構造：
Figure 2019169219000001
 （配列番号２０２１）
に従う、又はその塩の形態である、修飾されたオリゴヌクレオチド。 The following chemical structure:
Figure 2019169219000001
 (SEQ ID NO: 2021)
A modified oligonucleotide according to, or in the form of a salt thereof. 塩がナトリウム塩又はカリウム塩である、請求項３に記載の修飾されたオリゴヌクレオチド。 The modified oligonucleotide according to claim 3, wherein the salt is a sodium salt or a potassium salt. アニオン形態が以下の化学構造：
Figure 2019169219000002
 （配列番号２０２１）
を有する、修飾されたオリゴヌクレオチド。 Chemical structure with the following anion morphology:
Figure 2019169219000002
 (SEQ ID NO: 2021)
A modified oligonucleotide having. 以下の化学構造：
Figure 2019169219000003
 （配列番号２０２１）
に従う、修飾されたオリゴヌクレオチド。 The following chemical structure:
Figure 2019169219000003
 (SEQ ID NO: 2021)
Modified oligonucleotide according to. 請求項１又は２に記載のオリゴマー化合物又はその塩、又は請求項３～６のいずれか１項に記載の修飾されたオリゴヌクレオチドを含む、医薬組成物。 A pharmaceutical composition comprising the oligomer compound or salt thereof according to claim 1 or 2, or the modified oligonucleotide according to any one of claims 3 to 6. 薬学的に許容される担体又は希釈剤をさらに含む、請求項７に記載の医薬組成物。 The pharmaceutical composition according to claim 7, further comprising a pharmaceutically acceptable carrier or diluent. 希釈剤が水又はリン酸緩衝食塩水（ＰＢＳ）である、請求項８に記載の医薬組成物。 The pharmaceutical composition according to claim 8, wherein the diluent is water or phosphate buffered saline (PBS). 治療に使用するための、請求項７～９のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 7 to 9, for use in treatment. ＩＲＦ４に関連するがんを治療するための、請求項７～１０のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 7 to 10, for treating a cancer associated with IRF4. がんが、血液がん、骨髄腫、多発性骨髄腫（ＭＭ）、Ｂ細胞悪性腫瘍、リンパ腫、Ｂ細胞リンパ腫、Ｔ細胞リンパ腫、又は白血病である、請求項１１に記載の医薬組成物。 The pharmaceutical composition according to claim 11, wherein the cancer is blood cancer, myeloma, multiple myeloma (MM), B-cell malignant tumor, lymphoma, B-cell lymphoma, T-cell lymphoma, or leukemia. がんが、多発性骨髄腫（ＭＭ）である、請求項１２に記載の医薬組成物。 The pharmaceutical composition according to claim 12, wherein the cancer is multiple myeloma (MM). がん細胞増殖、腫瘍増殖、又は転移を阻害又は低減する、請求項７～１３のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 7 to 13, which inhibits or reduces cancer cell growth, tumor growth, or metastasis.
JP2020545734A 2018-03-02 2019-03-01 Regulators of IRF4 expression Active JP7239597B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2023031616A JP2023071856A (en) 2018-03-02 2023-03-02 Modulators of irf4 expression

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201862637981P 2018-03-02 2018-03-02
US62/637,981 2018-03-02
PCT/US2019/020201 WO2019169219A1 (en) 2018-03-02 2019-03-01 Modulators of irf4 expression

Related Child Applications (1)

Application Number Title Priority Date Filing Date
JP2023031616A Division JP2023071856A (en) 2018-03-02 2023-03-02 Modulators of irf4 expression

Publications (3)

Publication Number Publication Date
JP2021514657A JP2021514657A (en) 2021-06-17
JPWO2019169219A5 true JPWO2019169219A5 (en) 2022-03-04
JP7239597B2 JP7239597B2 (en) 2023-03-14

Family

ID=67805919

Family Applications (2)

Application Number Title Priority Date Filing Date
JP2020545734A Active JP7239597B2 (en) 2018-03-02 2019-03-01 Regulators of IRF4 expression
JP2023031616A Pending JP2023071856A (en) 2018-03-02 2023-03-02 Modulators of irf4 expression

Family Applications After (1)

Application Number Title Priority Date Filing Date
JP2023031616A Pending JP2023071856A (en) 2018-03-02 2023-03-02 Modulators of irf4 expression

Country Status (13)

Country Link
US (2) US11241451B2 (en)
EP (1) EP3758704A4 (en)
JP (2) JP7239597B2 (en)
KR (1) KR20200128064A (en)
CN (1) CN111886011B (en)
AU (1) AU2019228607B2 (en)
BR (1) BR112020016001A2 (en)
CA (1) CA3092574A1 (en)
IL (1) IL276684A (en)
MX (1) MX2020009147A (en)
PE (1) PE20210109A1 (en)
SG (1) SG11202007474YA (en)
WO (1) WO2019169219A1 (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11332733B2 (en) 2018-02-12 2022-05-17 lonis Pharmaceuticals, Inc. Modified compounds and uses thereof
JP7239597B2 (en) 2018-03-02 2023-03-14 アイオーニス ファーマシューティカルズ， インコーポレーテッド Regulators of IRF4 expression
WO2021092459A1 (en) * 2019-11-08 2021-05-14 Ionis Pharmaceuticals, Inc. Compounds and methods for reducing spdef expression
WO2022204714A1 (en) * 2021-03-24 2022-09-29 Kansas State University Research Foundation Zinc-based physionanocomposites and methods of use thereof

Family Cites Families (183)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3687808A (en) 1969-08-14 1972-08-29 Univ Leland Stanford Junior Synthetic polynucleotides
US5132418A (en) 1980-02-29 1992-07-21 University Patents, Inc. Process for preparing polynucleotides
US4500707A (en) 1980-02-29 1985-02-19 University Patents, Inc. Nucleosides useful in the preparation of polynucleotides
US4469863A (en) 1980-11-12 1984-09-04 Ts O Paul O P Nonionic nucleic acid alkyl and aryl phosphonates and processes for manufacture and use thereof
US4973679A (en) 1981-03-27 1990-11-27 University Patents, Inc. Process for oligonucleo tide synthesis using phosphormidite intermediates
US4415732A (en) 1981-03-27 1983-11-15 University Patents, Inc. Phosphoramidite compounds and processes
US5023243A (en) 1981-10-23 1991-06-11 Molecular Biosystems, Inc. Oligonucleotide therapeutic agent and method of making same
US4476301A (en) 1982-04-29 1984-10-09 Centre National De La Recherche Scientifique Oligonucleotides, a process for preparing the same and their application as mediators of the action of interferon
DE3329892A1 (en) 1983-08-18 1985-03-07 Köster, Hubert, Prof. Dr., 2000 Hamburg METHOD FOR PRODUCING OLIGONUCLEOTIDES
US5118800A (en) 1983-12-20 1992-06-02 California Institute Of Technology Oligonucleotides possessing a primary amino group in the terminal nucleotide
USRE34036E (en) 1984-06-06 1992-08-18 National Research Development Corporation Data transmission using a transparent tone-in band system
US5550111A (en) 1984-07-11 1996-08-27 Temple University-Of The Commonwealth System Of Higher Education Dual action 2',5'-oligoadenylate antiviral derivatives and uses thereof
FR2567892B1 (en) 1984-07-19 1989-02-17 Centre Nat Rech Scient NOVEL OLIGONUCLEOTIDES, THEIR PREPARATION PROCESS AND THEIR APPLICATIONS AS MEDIATORS IN DEVELOPING THE EFFECTS OF INTERFERONS
US5367066A (en) 1984-10-16 1994-11-22 Chiron Corporation Oligonucleotides with selectably cleavable and/or abasic sites
FR2575751B1 (en) 1985-01-08 1987-04-03 Pasteur Institut NOVEL ADENOSINE DERIVATIVE NUCLEOSIDES, THEIR PREPARATION AND THEIR BIOLOGICAL APPLICATIONS
US5034506A (en) 1985-03-15 1991-07-23 Anti-Gene Development Group Uncharged morpholino-based polymers having achiral intersubunit linkages
US5405938A (en) 1989-12-20 1995-04-11 Anti-Gene Development Group Sequence-specific binding polymers for duplex nucleic acids
US5235033A (en) 1985-03-15 1993-08-10 Anti-Gene Development Group Alpha-morpholino ribonucleoside derivatives and polymers thereof
US5506337A (en) 1985-03-15 1996-04-09 Antivirals Inc. Morpholino-subunit combinatorial library and method
US5185444A (en) 1985-03-15 1993-02-09 Anti-Gene Deveopment Group Uncharged morpolino-based polymers having phosphorous containing chiral intersubunit linkages
US5166315A (en) 1989-12-20 1992-11-24 Anti-Gene Development Group Sequence-specific binding polymers for duplex nucleic acids
EP0260032B1 (en) 1986-09-08 1994-01-26 Ajinomoto Co., Inc. Compounds for the cleavage at a specific position of RNA, oligomers employed for the formation of said compounds, and starting materials for the synthesis of said oligomers
US5264423A (en) 1987-03-25 1993-11-23 The United States Of America As Represented By The Department Of Health And Human Services Inhibitors for replication of retroviruses and for the expression of oncogene products
US5276019A (en) 1987-03-25 1994-01-04 The United States Of America As Represented By The Department Of Health And Human Services Inhibitors for replication of retroviruses and for the expression of oncogene products
JP2828642B2 (en) 1987-06-24 1998-11-25 ハワード フローレイ インスティテュト オブ イクスペリメンタル フィジオロジー アンド メディシン Nucleoside derivative
US4924624A (en) 1987-10-22 1990-05-15 Temple University-Of The Commonwealth System Of Higher Education 2,',5'-phosphorothioate oligoadenylates and plant antiviral uses thereof
US5188897A (en) 1987-10-22 1993-02-23 Temple University Of The Commonwealth System Of Higher Education Encapsulated 2',5'-phosphorothioate oligoadenylates
ATE151467T1 (en) 1987-11-30 1997-04-15 Univ Iowa Res Found DNA MOLECULES STABILIZED BY MODIFICATIONS TO THE 3'-TERMINAL PHOSPHODIESTER BOND, THEIR USE AS NUCLEIC ACID PROBE AND AS THERAPEUTIC AGENTS FOR INHIBITING THE EXPRESSION OF SPECIFIC TARGET GENES
US5403711A (en) 1987-11-30 1995-04-04 University Of Iowa Research Foundation Nucleic acid hybridization and amplification method for detection of specific sequences in which a complementary labeled nucleic acid probe is cleaved
JPH03503894A (en) 1988-03-25 1991-08-29 ユニバーシィティ　オブ　バージニア　アランミ　パテンツ　ファウンデイション Oligonucleotide N-alkylphosphoramidate
US5278302A (en) 1988-05-26 1994-01-11 University Patents, Inc. Polynucleotide phosphorodithioates
US5216141A (en) 1988-06-06 1993-06-01 Benner Steven A Oligonucleotide analogs containing sulfur linkages
US5175273A (en) 1988-07-01 1992-12-29 Genentech, Inc. Nucleic acid intercalating agents
US5194599A (en) 1988-09-23 1993-03-16 Gilead Sciences, Inc. Hydrogen phosphonodithioate compositions
US5256775A (en) 1989-06-05 1993-10-26 Gilead Sciences, Inc. Exonuclease-resistant oligonucleotides
US5134066A (en) 1989-08-29 1992-07-28 Monsanto Company Improved probes using nucleosides containing 3-dezauracil analogs
US5591722A (en) 1989-09-15 1997-01-07 Southern Research Institute 2'-deoxy-4'-thioribonucleosides and their antiviral activity
US5399676A (en) 1989-10-23 1995-03-21 Gilead Sciences Oligonucleotides with inverted polarity
US5721218A (en) 1989-10-23 1998-02-24 Gilead Sciences, Inc. Oligonucleotides with inverted polarity
US5264564A (en) 1989-10-24 1993-11-23 Gilead Sciences Oligonucleotide analogs with novel linkages
US5264562A (en) 1989-10-24 1993-11-23 Gilead Sciences, Inc. Oligonucleotide analogs with novel linkages
EP0942000B1 (en) 1989-10-24 2004-06-23 Isis Pharmaceuticals, Inc. 2'-Modified oligonucleotides
US5177198A (en) 1989-11-30 1993-01-05 University Of N.C. At Chapel Hill Process for preparing oligoribonucleoside and oligodeoxyribonucleoside boranophosphates
US5130302A (en) 1989-12-20 1992-07-14 Boron Bilogicals, Inc. Boronated nucleoside, nucleotide and oligonucleotide compounds, compositions and methods for using same
US5646265A (en) 1990-01-11 1997-07-08 Isis Pharmceuticals, Inc. Process for the preparation of 2'-O-alkyl purine phosphoramidites
US5859221A (en) 1990-01-11 1999-01-12 Isis Pharmaceuticals, Inc. 2'-modified oligonucleotides
US5670633A (en) 1990-01-11 1997-09-23 Isis Pharmaceuticals, Inc. Sugar modified oligonucleotides that detect and modulate gene expression
US7101993B1 (en) 1990-01-11 2006-09-05 Isis Pharmaceuticals, Inc. Oligonucleotides containing 2′-O-modified purines
US6005087A (en) 1995-06-06 1999-12-21 Isis Pharmaceuticals, Inc. 2'-modified oligonucleotides
US5623065A (en) 1990-08-13 1997-04-22 Isis Pharmaceuticals, Inc. Gapped 2' modified oligonucleotides
US5459255A (en) 1990-01-11 1995-10-17 Isis Pharmaceuticals, Inc. N-2 substituted purines
US5587470A (en) 1990-01-11 1996-12-24 Isis Pharmaceuticals, Inc. 3-deazapurines
US5681941A (en) 1990-01-11 1997-10-28 Isis Pharmaceuticals, Inc. Substituted purines and oligonucleotide cross-linking
US5587361A (en) 1991-10-15 1996-12-24 Isis Pharmaceuticals, Inc. Oligonucleotides having phosphorothioate linkages of high chiral purity
US5457191A (en) 1990-01-11 1995-10-10 Isis Pharmaceuticals, Inc. 3-deazapurines
US5149797A (en) 1990-02-15 1992-09-22 The Worcester Foundation For Experimental Biology Method of site-specific alteration of rna and production of encoded polypeptides
US5220007A (en) 1990-02-15 1993-06-15 The Worcester Foundation For Experimental Biology Method of site-specific alteration of RNA and production of encoded polypeptides
US5321131A (en) 1990-03-08 1994-06-14 Hybridon, Inc. Site-specific functionalization of oligodeoxynucleotides for non-radioactive labelling
US5470967A (en) 1990-04-10 1995-11-28 The Dupont Merck Pharmaceutical Company Oligonucleotide analogs with sulfamate linkages
GB9009980D0 (en) 1990-05-03 1990-06-27 Amersham Int Plc Phosphoramidite derivatives,their preparation and the use thereof in the incorporation of reporter groups on synthetic oligonucleotides
ES2116977T3 (en) 1990-05-11 1998-08-01 Microprobe Corp SOLID SUPPORTS FOR NUCLEIC ACID HYBRIDIZATION TESTS AND METHODS TO IMMOBILIZE OLIGONUCLEOTIDES IN A COVALENT WAY.
US5489677A (en) 1990-07-27 1996-02-06 Isis Pharmaceuticals, Inc. Oligonucleoside linkages containing adjacent oxygen and nitrogen atoms
BR9106702A (en) 1990-07-27 1993-06-08 Isis Pharmaceuticals Inc ANALOG OF OLIGONUCLEOTIDEOS AND PROCESSES TO MODULATE THE PRODUCTION OF A PROTEIN BY AN ORGANISM AND TO TREAT AN ORGANISM
US5602240A (en) 1990-07-27 1997-02-11 Ciba Geigy Ag. Backbone modified oligonucleotide analogs
US5608046A (en) 1990-07-27 1997-03-04 Isis Pharmaceuticals, Inc. Conjugated 4'-desmethyl nucleoside analog compounds
US5378825A (en) 1990-07-27 1995-01-03 Isis Pharmaceuticals, Inc. Backbone modified oligonucleotide analogs
US5610289A (en) 1990-07-27 1997-03-11 Isis Pharmaceuticals, Inc. Backbone modified oligonucleotide analogues
US5677437A (en) 1990-07-27 1997-10-14 Isis Pharmaceuticals, Inc. Heteroatomic oligonucleoside linkages
US5541307A (en) 1990-07-27 1996-07-30 Isis Pharmaceuticals, Inc. Backbone modified oligonucleotide analogs and solid phase synthesis thereof
US5623070A (en) 1990-07-27 1997-04-22 Isis Pharmaceuticals, Inc. Heteroatomic oligonucleoside linkages
US5618704A (en) 1990-07-27 1997-04-08 Isis Pharmacueticals, Inc. Backbone-modified oligonucleotide analogs and preparation thereof through radical coupling
US5223618A (en) 1990-08-13 1993-06-29 Isis Pharmaceuticals, Inc. 4'-desmethyl nucleoside analog compounds
US5386023A (en) 1990-07-27 1995-01-31 Isis Pharmaceuticals Backbone modified oligonucleotide analogs and preparation thereof through reductive coupling
IL113519A (en) 1990-08-03 1997-11-20 Sterling Winthrop Inc Oligonucleoside sequences of from about 6 to about 200 bases having a three atom internucleoside linkage, their preparation and pharmaceutical compositions for inhibiting gene expression containing said oligonucleosides
US5177196A (en) 1990-08-16 1993-01-05 Microprobe Corporation Oligo (α-arabinofuranosyl nucleotides) and α-arabinofuranosyl precursors thereof
US5214134A (en) 1990-09-12 1993-05-25 Sterling Winthrop Inc. Process of linking nucleosides with a siloxane bridge
US5561225A (en) 1990-09-19 1996-10-01 Southern Research Institute Polynucleotide analogs containing sulfonate and sulfonamide internucleoside linkages
CA2092002A1 (en) 1990-09-20 1992-03-21 Mark Matteucci Modified internucleoside linkages
US5432272A (en) 1990-10-09 1995-07-11 Benner; Steven A. Method for incorporating into a DNA or RNA oligonucleotide using nucleotides bearing heterocyclic bases
US6582908B2 (en) 1990-12-06 2003-06-24 Affymetrix, Inc. Oligonucleotides
US5948903A (en) 1991-01-11 1999-09-07 Isis Pharmaceuticals, Inc. Synthesis of 3-deazapurines
US5672697A (en) 1991-02-08 1997-09-30 Gilead Sciences, Inc. Nucleoside 5'-methylene phosphonates
US7015315B1 (en) 1991-12-24 2006-03-21 Isis Pharmaceuticals, Inc. Gapped oligonucleotides
US5571799A (en) 1991-08-12 1996-11-05 Basco, Ltd. (2'-5') oligoadenylate analogues useful as inhibitors of host-v5.-graft response
DE59208572D1 (en) 1991-10-17 1997-07-10 Ciba Geigy Ag Bicyclic nucleosides, oligonucleotides, processes for their preparation and intermediates
US5594121A (en) 1991-11-07 1997-01-14 Gilead Sciences, Inc. Enhanced triple-helix and double-helix formation with oligomers containing modified purines
JP3739785B2 (en) 1991-11-26 2006-01-25 アイシス ファーマシューティカルズ，インコーポレイティド Enhanced triple and double helix shaping using oligomers containing modified pyrimidines
TW393513B (en) 1991-11-26 2000-06-11 Isis Pharmaceuticals Inc Enhanced triple-helix and double-helix formation with oligomers containing modified pyrimidines
US5484908A (en) 1991-11-26 1996-01-16 Gilead Sciences, Inc. Oligonucleotides containing 5-propynyl pyrimidines
US5792608A (en) 1991-12-12 1998-08-11 Gilead Sciences, Inc. Nuclease stable and binding competent oligomers and methods for their use
US5359044A (en) 1991-12-13 1994-10-25 Isis Pharmaceuticals Cyclobutyl oligonucleotide surrogates
US5700922A (en) 1991-12-24 1997-12-23 Isis Pharmaceuticals, Inc. PNA-DNA-PNA chimeric macromolecules
FR2687679B1 (en) 1992-02-05 1994-10-28 Centre Nat Rech Scient OLIGOTHIONUCLEOTIDES.
US5633360A (en) 1992-04-14 1997-05-27 Gilead Sciences, Inc. Oligonucleotide analogs capable of passive cell membrane permeation
US5434257A (en) 1992-06-01 1995-07-18 Gilead Sciences, Inc. Binding compentent oligomers containing unsaturated 3',5' and 2',5' linkages
EP0577558A2 (en) 1992-07-01 1994-01-05 Ciba-Geigy Ag Carbocyclic nucleosides having bicyclic rings, oligonucleotides therefrom, process for their preparation, their use and intermediates
US5652355A (en) 1992-07-23 1997-07-29 Worcester Foundation For Experimental Biology Hybrid oligonucleotide phosphorothioates
US5476925A (en) 1993-02-01 1995-12-19 Northwestern University Oligodeoxyribonucleotides including 3'-aminonucleoside-phosphoramidate linkages and terminal 3'-amino groups
GB9304620D0 (en) 1993-03-06 1993-04-21 Ciba Geigy Ag Compounds
GB9304618D0 (en) 1993-03-06 1993-04-21 Ciba Geigy Ag Chemical compounds
CA2159631A1 (en) 1993-03-30 1994-10-13 Sanofi Acyclic nucleoside analogs and oligonucleotide sequences containing them
WO1994022891A1 (en) 1993-03-31 1994-10-13 Sterling Winthrop Inc. Oligonucleotides with amide linkages replacing phosphodiester linkages
US5502177A (en) 1993-09-17 1996-03-26 Gilead Sciences, Inc. Pyrimidine derivatives for labeled binding partners
US5801154A (en) 1993-10-18 1998-09-01 Isis Pharmaceuticals, Inc. Antisense oligonucleotide modulation of multidrug resistance-associated protein
US5457187A (en) 1993-12-08 1995-10-10 Board Of Regents University Of Nebraska Oligonucleotides containing 5-fluorouracil
US5446137B1 (en) 1993-12-09 1998-10-06 Behringwerke Ag Oligonucleotides containing 4'-substituted nucleotides
DE69425903T2 (en) 1993-12-09 2001-02-15 Thomas Jefferson University Ph CONNECTIONS AND METHOD FOR LOCATION-SPECIFIC MUTATION IN EUKARYOTIC CELLS
US5519134A (en) 1994-01-11 1996-05-21 Isis Pharmaceuticals, Inc. Pyrrolidine-containing monomers and oligomers
US5596091A (en) 1994-03-18 1997-01-21 The Regents Of The University Of California Antisense oligonucleotides comprising 5-aminoalkyl pyrimidine nucleotides
US5627053A (en) 1994-03-29 1997-05-06 Ribozyme Pharmaceuticals, Inc. 2'deoxy-2'-alkylnucleotide containing nucleic acid
US5625050A (en) 1994-03-31 1997-04-29 Amgen Inc. Modified oligonucleotides and intermediates useful in nucleic acid therapeutics
US5646269A (en) 1994-04-28 1997-07-08 Gilead Sciences, Inc. Method for oligonucleotide analog synthesis
US5525711A (en) 1994-05-18 1996-06-11 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Pteridine nucleotide analogs as fluorescent DNA probes
US5597909A (en) 1994-08-25 1997-01-28 Chiron Corporation Polynucleotide reagents containing modified deoxyribose moieties, and associated methods of synthesis and use
US5652356A (en) 1995-08-17 1997-07-29 Hybridon, Inc. Inverted chimeric and hybrid oligonucleotides
WO1997020563A1 (en) 1995-11-22 1997-06-12 The Johns-Hopkins University Ligands to enhance cellular uptake of biomolecules
US6245562B1 (en) 1996-05-28 2001-06-12 The Trustees Of Columbia University In The City Of New York Identification of genes altered in multiple myeloma
US7875733B2 (en) 2003-09-18 2011-01-25 Isis Pharmaceuticals, Inc. Oligomeric compounds comprising 4′-thionucleosides for use in gene modulation
US6770748B2 (en) 1997-03-07 2004-08-03 Takeshi Imanishi Bicyclonucleoside and oligonucleotide analogue
USRE44779E1 (en) 1997-03-07 2014-02-25 Santaris Pharma A/S Bicyclonucleoside and oligonucleotide analogues
US7572582B2 (en) 1997-09-12 2009-08-11 Exiqon A/S Oligonucleotide analogues
US20030228597A1 (en) 1998-04-13 2003-12-11 Cowsert Lex M. Identification of genetic targets for modulation by oligonucleotides and generation of oligonucleotides for gene modulation
US6300319B1 (en) 1998-06-16 2001-10-09 Isis Pharmaceuticals, Inc. Targeted oligonucleotide conjugates
US6043352A (en) 1998-08-07 2000-03-28 Isis Pharmaceuticals, Inc. 2'-O-Dimethylaminoethyloxyethyl-modified oligonucleotides
KR100782896B1 (en) 1999-05-04 2007-12-06 엑시콘 에이/에스 L-Ribo-LNA analogues
US6525191B1 (en) 1999-05-11 2003-02-25 Kanda S. Ramasamy Conformationally constrained L-nucleosides
US9029523B2 (en) 2000-04-26 2015-05-12 Ceres, Inc. Promoter, promoter control elements, and combinations, and uses thereof
US7491805B2 (en) 2001-05-18 2009-02-17 Sirna Therapeutics, Inc. Conjugates and compositions for cellular delivery
WO2001077384A2 (en) 2000-04-07 2001-10-18 Epigenomics Ag Detection of single nucleotide polymorphisms (snp's) and cytosine-methylations
US6426220B1 (en) 2000-10-30 2002-07-30 Isis Pharmaceuticals, Inc. Antisense modulation of calreticulin expression
AU2002217980A1 (en) 2000-12-01 2002-06-11 Cell Works Inc. Conjugates of glycosylated/galactosylated peptide
US20030158403A1 (en) 2001-07-03 2003-08-21 Isis Pharmaceuticals, Inc. Nuclease resistant chimeric oligonucleotides
US20030175906A1 (en) 2001-07-03 2003-09-18 Muthiah Manoharan Nuclease resistant chimeric oligonucleotides
WO2004044139A2 (en) 2002-11-05 2004-05-27 Isis Parmaceuticals, Inc. Modified oligonucleotides for use in rna interference
AU2003291753B2 (en) 2002-11-05 2010-07-08 Isis Pharmaceuticals, Inc. Polycyclic sugar surrogate-containing oligomeric compounds and compositions for use in gene modulation
JP2006507841A (en) 2002-11-14 2006-03-09 ダーマコン， インコーポレイテッド Functional and ultrafunctional siRNA
US7217807B2 (en) 2002-11-26 2007-05-15 Rosetta Genomics Ltd Bioinformatically detectable group of novel HIV regulatory genes and uses thereof
US20080318210A1 (en) 2003-08-27 2008-12-25 Rosetta Genomics Bioinformatically detectable group of novel regulatory viral and viral associated oligonucleotides and uses thereof
US7723509B2 (en) 2003-04-17 2010-05-25 Alnylam Pharmaceuticals IRNA agents with biocleavable tethers
US7888497B2 (en) 2003-08-13 2011-02-15 Rosetta Genomics Ltd. Bioinformatically detectable group of novel regulatory oligonucleotides and uses thereof
ES2382807T3 (en) 2003-08-28 2012-06-13 Takeshi Imanishi New artificial nucleic acids of the N-O link type with cross-linking
CA2566286A1 (en) 2004-05-11 2005-12-08 Rnai Co., Ltd. Polynucleotide causing rna interfere and method of regulating gene expression with the use of the same
US7687616B1 (en) 2004-05-14 2010-03-30 Rosetta Genomics Ltd Small molecules modulating activity of micro RNA oligonucleotides and micro RNA targets and uses thereof
US20060148740A1 (en) 2005-01-05 2006-07-06 Prosensa B.V. Mannose-6-phosphate receptor mediated gene transfer into muscle cells
KR20130042043A (en) 2006-01-27 2013-04-25 아이시스 파마수티컬즈 인코포레이티드 6-modified bicyclic nucleic acid analogs
US7569686B1 (en) 2006-01-27 2009-08-04 Isis Pharmaceuticals, Inc. Compounds and methods for synthesis of bicyclic nucleic acid analogs
US8178503B2 (en) 2006-03-03 2012-05-15 International Business Machines Corporation Ribonucleic acid interference molecules and binding sites derived by analyzing intergenic and intronic regions of genomes
DK2066684T3 (en) 2006-05-11 2012-10-22 Isis Pharmaceuticals Inc 5'-Modified Bicyclic Nucleic Acid Analogs
US7666854B2 (en) 2006-05-11 2010-02-23 Isis Pharmaceuticals, Inc. Bis-modified bicyclic nucleic acid analogs
EP2410053B2 (en) 2006-10-18 2020-07-15 Ionis Pharmaceuticals, Inc. Antisense compounds
WO2008101157A1 (en) 2007-02-15 2008-08-21 Isis Pharmaceuticals, Inc. 5'-substituted-2'-f modified nucleosides and oligomeric compounds prepared therefrom
US20100105134A1 (en) 2007-03-02 2010-04-29 Mdrna, Inc. Nucleic acid compounds for inhibiting gene expression and uses thereof
WO2008150729A2 (en) 2007-05-30 2008-12-11 Isis Pharmaceuticals, Inc. N-substituted-aminomethylene bridged bicyclic nucleic acid analogs
WO2008154401A2 (en) 2007-06-08 2008-12-18 Isis Pharmaceuticals, Inc. Carbocyclic bicyclic nucleic acid analogs
WO2009006478A2 (en) 2007-07-05 2009-01-08 Isis Pharmaceuticals, Inc. 6-disubstituted bicyclic nucleic acid analogs
EP2188298B1 (en) 2007-08-15 2013-09-18 Isis Pharmaceuticals, Inc. Tetrahydropyran nucleic acid analogs
US8546556B2 (en) 2007-11-21 2013-10-01 Isis Pharmaceuticals, Inc Carbocyclic alpha-L-bicyclic nucleic acid analogs
AU2008333811B2 (en) 2007-12-04 2014-05-01 Alnylam Pharmaceuticals, Inc. Carbohydrate conjugates as delivery agents for oligonucleotides
WO2009078931A2 (en) 2007-12-10 2009-06-25 Brandeis University Irf as a tumor suppressor and uses thereof
EP2265627A2 (en) 2008-02-07 2010-12-29 Isis Pharmaceuticals, Inc. Bicyclic cyclohexitol nucleic acid analogs
CA2722416A1 (en) * 2008-04-22 2009-10-29 The Washington University Method for predicting risk of metastasis
WO2010036698A1 (en) 2008-09-24 2010-04-01 Isis Pharmaceuticals, Inc. Substituted alpha-l-bicyclic nucleosides
US20100324119A1 (en) 2009-05-18 2010-12-23 Mayo Foundation For Medical Education And Research Reducing irf4, dusp22, or flj43663 polypeptide expression
WO2011005765A1 (en) 2009-07-06 2011-01-13 Alnylam Pharmaceuticals, Inc. Bioprocessing
US9012421B2 (en) 2009-08-06 2015-04-21 Isis Pharmaceuticals, Inc. Bicyclic cyclohexose nucleic acid analogs
KR101878501B1 (en) * 2010-01-04 2018-08-07 큐알엔에이, 인크. Treatment of interferon regulatory factor 8 (irf8) related diseases by inhibition of natural antisense transcript to irf8
WO2011133876A2 (en) 2010-04-22 2011-10-27 Alnylam Pharmaceuticals, Inc. Oligonucleotides comprising acyclic and abasic nucleosides and analogs
US10316362B2 (en) 2010-05-18 2019-06-11 Natera, Inc. Methods for simultaneous amplification of target loci
US9290760B2 (en) 2010-09-15 2016-03-22 Alnylam Pharmaceuticals, Inc. Modified iRNA agents
US10017764B2 (en) 2011-02-08 2018-07-10 Ionis Pharmaceuticals, Inc. Oligomeric compounds comprising bicyclic nucleotides and uses thereof
US10023861B2 (en) 2011-08-29 2018-07-17 Ionis Pharmaceuticals, Inc. Oligomer-conjugate complexes and their use
WO2013159108A2 (en) * 2012-04-20 2013-10-24 Isis Pharmaceuticals, Inc. Oligomeric compounds comprising bicyclic nucleotides and uses thereof
WO2013173637A1 (en) 2012-05-16 2013-11-21 Rana Therapeutics, Inc. Compositions and methods for modulating gene expression
WO2013173635A1 (en) 2012-05-16 2013-11-21 Rana Therapeutics, Inc. Compositions and methods for modulating gene expression
JP2015518713A (en) 2012-05-16 2015-07-06 ラナ セラピューティクス インコーポレイテッド Compositions and methods for modulating UTRN expression
WO2014059353A2 (en) * 2012-10-11 2014-04-17 Isis Pharmaceuticals, Inc. Oligomeric compounds comprising bicyclic nucleosides and uses thereof
US20150291958A1 (en) 2012-11-15 2015-10-15 Roche Innovation Center Copenhagen A/S Anti apob antisense conjugate compounds
AU2014259759B2 (en) 2013-05-01 2020-06-18 Ionis Pharmaceuticals, Inc. Compositions and methods
CA2964161A1 (en) * 2014-10-10 2016-04-14 Dana-Farber Cancer Institute, Inc. Methods for discovering therapeutics that alter the stability of target proteins
JP6833705B2 (en) * 2015-04-03 2021-02-24 アイオーニス ファーマシューティカルズ， インコーポレーテッドＩｏｎｉｓ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． Compounds and methods for regulating TMPRSS6 expression
GB201507926D0 (en) 2015-05-08 2015-06-24 Proqr Therapeutics N V Improved treatments using oligonucleotides
EP3353328A4 (en) * 2015-09-24 2019-06-12 Ionis Pharmaceuticals, Inc. Modulators of kras expression
JP7239597B2 (en) 2018-03-02 2023-03-14 アイオーニス ファーマシューティカルズ， インコーポレーテッド Regulators of IRF4 expression

Similar Documents

Publication Publication Date Title
JP2018528781A5 (en)
JP2020115865A5 (en)
EP2356129B1 (en) Substituted alpha-l-bicyclic nucleosides
EP2173760B1 (en) Carbocyclic bicyclic nucleic acid analogs
JP4267233B2 (en) Oligonucleotides N3 '→ P5' thiophosphoramidates: their synthesis and use
AU2007211080B2 (en) 6-modified bicyclic nucleic acid analogs
US9428750B2 (en) Oligomeric compounds comprising tricyclic nucleosides and methods for their use
US9688707B2 (en) Bicyclic morpholino compounds and oligomeric compounds prepared therefrom
JP2022106727A5 (en)
US20130041011A1 (en) Base modified bicyclic nucleosides and oligomeric compounds prepared therefrom
AU2022202991A1 (en) Organic compositions to treat KRAS-related diseases
JP2009108095A (en) Oligonucleotide n3'->p5' phosphoramidates: synthesis and compound; hybridization and nuclease resistance properties
TW201639962A (en) RNA interference agents
JPH0898700A (en) Sugar-modified oligonucleotide for detecting and modulating expression of gene
JP2020511155A5 (en)
US20160122372A1 (en) Tricyclic nucleosides and oligomeric compounds prepared therefrom
JPWO2019169219A5 (en)
US20160186174A1 (en) Substituted morpholino compounds analogs thereof and oligomeric compounds prepared therefrom
RU2008121953A (en) IRNA INFLUENZA VIRUS REPLICATION INHIBITION
CN111902537A (en) Modulators of DNM2 expression
Guga et al. Enhanced P-stereodependent stability of complexes formed by phosphorothioate oligonucleotides due to involvement of sulfur as strong hydrogen bond acceptor
JPWO2019204743A5 (en)
JPH1135595A (en) Antisense oligonucleotide and carcinostatic agent using the same
JPWO2019200172A5 (en)
JPWO2019140236A5 (en)