HRP20181022T1 - Analozi oligonukleotida koji ciljaju ljudski lmna - Google Patents
Analozi oligonukleotida koji ciljaju ljudski lmna Download PDFInfo
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- HRP20181022T1 HRP20181022T1 HRP20181022TT HRP20181022T HRP20181022T1 HR P20181022 T1 HRP20181022 T1 HR P20181022T1 HR P20181022T T HRP20181022T T HR P20181022TT HR P20181022 T HRP20181022 T HR P20181022T HR P20181022 T1 HRP20181022 T1 HR P20181022T1
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- 108091034117 Oligonucleotide Proteins 0.000 title claims 22
- 230000008685 targeting Effects 0.000 title claims 11
- 101150077556 LMNA gene Proteins 0.000 title 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 13
- 239000001257 hydrogen Substances 0.000 claims 13
- 125000000217 alkyl group Chemical group 0.000 claims 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 7
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 claims 6
- 150000002431 hydrogen Chemical class 0.000 claims 6
- 125000005647 linker group Chemical group 0.000 claims 6
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims 6
- 108010051109 Cell-Penetrating Peptides Proteins 0.000 claims 5
- 102000020313 Cell-Penetrating Peptides Human genes 0.000 claims 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims 4
- 239000000074 antisense oligonucleotide Substances 0.000 claims 4
- 238000012230 antisense oligonucleotides Methods 0.000 claims 4
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 claims 4
- 125000003545 alkoxy group Chemical group 0.000 claims 3
- 125000003118 aryl group Chemical group 0.000 claims 3
- 229910052799 carbon Inorganic materials 0.000 claims 3
- 125000000623 heterocyclic group Chemical group 0.000 claims 3
- 229910052760 oxygen Inorganic materials 0.000 claims 3
- 229910052717 sulfur Inorganic materials 0.000 claims 3
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims 2
- 239000004471 Glycine Substances 0.000 claims 2
- 101001003584 Homo sapiens Prelamin-A/C Proteins 0.000 claims 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims 2
- 102100026531 Prelamin-A/C Human genes 0.000 claims 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims 2
- 125000003282 alkyl amino group Chemical group 0.000 claims 2
- 235000001014 amino acid Nutrition 0.000 claims 2
- 150000001413 amino acids Chemical class 0.000 claims 2
- 229960002684 aminocaproic acid Drugs 0.000 claims 2
- 125000004429 atom Chemical group 0.000 claims 2
- 229940000635 beta-alanine Drugs 0.000 claims 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims 2
- 235000018417 cysteine Nutrition 0.000 claims 2
- 125000001072 heteroaryl group Chemical group 0.000 claims 2
- 108020004999 messenger RNA Proteins 0.000 claims 2
- 229910052698 phosphorus Inorganic materials 0.000 claims 2
- 239000011574 phosphorus Substances 0.000 claims 2
- 125000004642 (C1-C12) alkoxy group Chemical group 0.000 claims 1
- MHCMWGPPLOSCJY-UHFFFAOYSA-N 4-$l^{1}-azanylmorpholine Chemical compound [N]N1CCOCC1 MHCMWGPPLOSCJY-UHFFFAOYSA-N 0.000 claims 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 239000004215 Carbon black (E152) Substances 0.000 claims 1
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims 1
- 125000000747 amidyl group Chemical group [H][N-]* 0.000 claims 1
- 125000004103 aminoalkyl group Chemical group 0.000 claims 1
- 125000003710 aryl alkyl group Chemical group 0.000 claims 1
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims 1
- 210000004899 c-terminal region Anatomy 0.000 claims 1
- 229940099352 cholate Drugs 0.000 claims 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 claims 1
- 125000004093 cyano group Chemical group *C#N 0.000 claims 1
- 229940009976 deoxycholate Drugs 0.000 claims 1
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 claims 1
- -1 guanidinyl Chemical group 0.000 claims 1
- 229930195733 hydrocarbon Natural products 0.000 claims 1
- 150000002430 hydrocarbons Chemical class 0.000 claims 1
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims 1
- 108020004707 nucleic acids Proteins 0.000 claims 1
- 150000007523 nucleic acids Chemical class 0.000 claims 1
- 102000039446 nucleic acids Human genes 0.000 claims 1
- 125000004043 oxo group Chemical group O=* 0.000 claims 1
- 125000004193 piperazinyl group Chemical group 0.000 claims 1
- IGFXRKMLLMBKSA-UHFFFAOYSA-N purine Chemical compound N1=C[N]C2=NC=NC2=C1 IGFXRKMLLMBKSA-UHFFFAOYSA-N 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 1
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- A61K31/713—Double-stranded nucleic acids or oligonucleotides
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Claims (13)
1. Protusmjerni oligonukleotid za smanjenje ekspresije abnormalno upletene LMNA mRNA, te oligonukleotid ima uglavnom nanabijenu okosnicu i sastavljen je od morfolino podjedinica i veza između podjedinica koje sadrže fosfor koje spajaju morfolino dušik jedne podjedinice na 5'-egzociklički ugljik susjedne podjedinice,
koji sadržava 25-40 baza, te
koji sadrži ciljajuću sekvencu koja sadrži bilo koju od SEQ ID NOs: 4, 5, 10, 11, 13, 14, i 16,
pri čemu je protusmjerni oligonukleotid kovalentno vezan na peptid koji prodire u stanicu i skupine poveznice, pri čemu je skupina poveznice odabrana iz niza koji čine glicin, cistein, prolin, 6-aminoheksanoična kiselina (Ahx), β-alanin (B), i Ahx-B, te peptid koji prodire u stanicu je odabran od SEQ ID NOs: 39-54.
2. Oligonukleotid prema zahtjevu 1, naznačen time da su morfolino podjedinice u oligonukleotidu povezane putem veza koje sadrže fosfor, u skladu sa sljedećom strukturom:
pri čemu Z je S ili O,
X = NR1R2 ili OR6,
Y = O ili NR7,
Pj je purin ili skupina sparivanja pirimidinske baze,
i svaka navedena veza je odabrana od:
(a) veze bez naboja (a), pri čemu svaki od R1, R2, R6, i R7 je neovisno odabran od vodika i nižeg alkila;
(b1) kationske veze (b1), pri čemu X = NR1R2 i Y= O, i NR1R2 predstavlja proizvoljno supstituiranu piperazino skupinu, tako da R1R2 = -CHRCHRN(R3)(R4)CHRCHR-, pri čemu
svaki R4 je H, CH3 ili nula, i
R3 je odabran od H, nižeg alkila, C(=NH)NH2, Z-L-NHC(=NH)NH2, i [C(O)CHR'NH]mH, pri čemu gdje Z je karbonil (C(O)) ili izravna veza, L je proizvoljna poveznica duljine do 18 atoma koja ima veze koje su odabrane od alkila, alkoksi, i alkilamino, R' je bočni lanac prirodno dobivene amino kiseline ili njegov homolog s jednim- ili dva- ugljika, i m je 1 do 6;
(b2) kationske veze (b2), pri čemu X = NR1R2 i Y = O, R1 = H ili CH3, i R2 = LNR3R4R5, pri čemu L, R3, i R4 su definirani kao gore, i R5 je H, niži alkil, ili niži (alkoksi)alkil; i
(b3) kationske veze (b3), pri čemu Y = NR7 i X = OR6, i R7 = LNR3R4R5, pri čemu L, R3, i R4 i R5 su definirani kao gore, i R6 je H ili niži alkil; i barem jedna navedena veza je odabrana od kationskih veza (b1), (b2), i (b3).
3. Oligonukleotid prema zahtjevu 2, naznačen time da
(i) svaki od R1 i R2, u vezama tipa (a), je metil;
(ii) barem jedna veza je tipa (b1), gdje svaki R je H, R4 je H, CH3, ili par elektrona, i R3 je odabran od H, CH3, C(=NH)NH2, i C(O)-L-NHC(=NH)NH2;
(iii) barem jedna veza je tipa (b1), gdje svaki R je H, R4 je par elektrona, i R3 je odabran od C(=NH)NH2 i C(O)-L-NHC(=NH)NH2;
(iv) barem jedna veza je tipa (b1), gdje svaki R je H, R4 je par elektrona, i R3 je odabran od C(=NH)NH2 i C(O)-L-NHC(=NH)NH2, i proizvoljno gdje R3 je C(O)-L-NHC(NH)NH2, i L je ugljikovodik koji ima strukturu -(CH2)n-, gdje n je 1 do 12; ili
(v) barem jedna veza je tipa (b1), gdje svaki R je H, i svaki od R3 i R4 je neovisno H ili CH3.
4. Oligonukleotid prema bilo kojem od zahtjeva 1-3, naznačen time da je peptid koji prodire u stanicu spojen na njegovom C-terminalnom kraju na 5' završetak ili 3' završetak oligonukleotida preko skupine poveznice.
5. Protusmjerni oligonukleotid, pri čemu oligonukleotid smanjuje ekspresiju abnormalno upletene LMNA mRNA, oligonukleotid sadrži okosnicu, te okosnica sadrži sekvencu morfolino prstenastih struktura povezane pomoću veza između podjedinica, veze između podjedinica spajaju 3'- završetak jedne morfolino prstenaste strukture na 5'-završetak susjedne morfolino prstenaste strukture, pri čemu je svaka morfolino prstenasta struktura vezana na skupinu koja sparuje bazu, tako da se oligonukleotid može vezati na način specifičan za sekvencu na ciljnu nukleinsku kiselinu, koja sadrži ciljajuću sekvencu koja obuhvaća bilo koju od SEQ ID NOS: 4, 5, 10, 11, 13, 14, i 16, pri čemu veze između podjedinica imaju sljedeću opću strukturu (I):
ili njegova sol ili izomer, te pri čemu je svaka od veza između podjedinica (I) neovisno veza (A) ili veza (B):
pri čemu za vezu (A):
W je, pri svakom pojavljivanju, neovisno S ili O;
X je, pri svakom pojavljivanju, neovisno -N(CH3)2, -NR1R2, -OR3 ili;
Y je, pri svakom pojavljivanju, neovisno O ili -NR2,
R1 je, pri svakom pojavljivanju, neovisno vodik ili metil;
R2 je, pri svakom pojavljivanju, neovisno vodik ili -LNR4R5R7;
R3 je, pri svakom pojavljivanju, neovisno vodik ili C1-C6 alkil;
R4 je, pri svakom pojavljivanju, neovisno vodik, metil, -C(=NH)NH2, -Z-L-NHC(=NH)NH2 ili -[C(O)CHR'NH]mH, gdje Z je karbonil (C(O)) ili izravna veza, R' je bočni lanac prirodno dobivene amino kiseline ili njegov homolog s jednim- ili dva- ugljika, i m je 1 do 6;
R5 je, pri svakom pojavljivanju, neovisno vodik, metil ili par elektrona;
R6 je, pri svakom pojavljivanju, neovisno vodik ili metil;
R7 je, pri svakom pojavljivanju, neovisno vodik C1-C6 alkil ili C1-C6 alkoksialkil;
L je je proizvoljna poveznica s duljinom do 18 atoma skupine alkil, alkoksi ili alkilamino, ili njihovih kombinacija; i
pri čemu za vezu (B):
W je, pri svakom pojavljivanju, neovisno S ili O;
X je, pri svakom pojavljivanju, neovisno -NR8R9 ili -OR3; i
Y je, pri svakom pojavljivanju, neovisno O ili -NR10, ili
Y i W su svaki O,
R8 je, pri svakom pojavljivanju, neovisno vodik ili C2-C12 alkil;
R9 je, pri svakom pojavljivanju, neovisno vodik, C1-C12 alkil, C1-C12 aralkil ili aril;
R10 je, pri svakom pojavljivanju, neovisno vodik, C1-C12 alkil ili -LNR4R5R7;
pri čemu R8 i R9 se mogu spojiti da tvore 5-18 člani mono ili biciklički heterocikal ili R8, R9 ili R3 se mogu spojiti s R10 da tvore 5-7 člani heterocikal, i pri čemu kada X je 4-piparazino, X ima sljedeću strukturu (III):
pri čemu:
R11 je, pri svakom pojavljivanju, neovisno C2-C12 alkil, C1-C12 aminoalkil, C1-C12 alkilkarbonil, aril, heteroaril ili heterociklil; i
R je, pri svakom pojavljivanju, neovisno par elektrona, vodik ili C1-C12 alkil; i
R12 je, pri svakom pojavljivanju, neovisno, vodik, C1-C12 alkil, C1-C12 aminoalkil, -NH2, -NR13R14, -NR13R14R15, C1-C12 alkilkarbonil, okso, -CN, trifluorometil, amidil, amidinil, amidinilalkil, amidinilalkilkarbonil gvanidinil, gvanidinilalkil, gvanidinilalkilkarbonil, kolat, deoksikolat, aril, heteroaril, heterocikal, -SR13 ili C1-C12 alkoksi, pri čemu R13, R14 i R15 su, pri svakom pojavljivanju, neovisno C1-C12 alkil;
pri čemu barem jedna od veza između podjedinica je veza (B), ili pri čemu svaka veza (B) ako postoji ima istu strukturu pri svakom pojavljivanju; i
pri čemu je protusmjerni oligonukleotid kovalentno vezan na peptid koji prodire u stanicu i skupinu poveznice, pri čemu je skupina poveznice odabrana iz skupa koji čine glicin, cistein, prolin, 6-aminoheksanoična kiselina (Ahx), β-alanin (B), i Ahx-B, a peptid koji prodire u stanicu je odabran od SEQ ID NOs: 39-54.
6. Oligonukleotid prema bilo kojem od zahtjeva 1-5, naznačen time da se ciljajuća sekvenca sastoji od bilo koje od SEQ ID NOs: 4, 5, 10, 11, 13, 14, i 16.
7. Oligonukleotid prema bilo kojem od zahtjeva 1-6, naznačen time da ciljajuća sekvenca je SEQ ID NO: 4.
8. Oligonukleotid prema bilo kojem od zahtjeva 1-6, naznačen time da ciljajuća sekvenca je SEQ ID NO: 5.
9. Oligonukleotid prema bilo kojem od zahtjeva 1-6, naznačen time da ciljajuća sekvenca je SEQ ID NO: 10.
10. Oligonukleotid prema bilo kojem od zahtjeva 1-6, naznačen time da ciljajuća sekvenca je SEQ ID NO: 11.
11. Oligonukleotid prema bilo kojem od zahtjeva 1-6, naznačen time da ciljajuća sekvenca je SEQ ID NO: 13.
12. Oligonukleotid prema bilo kojem od zahtjeva 1-6, naznačen time da ciljajuća sekvenca je SEQ ID NO: 14.
13. Oligonukleotid prema bilo kojem od zahtjeva 1-6, naznačen time da ciljajuća sekvenca je SEQ ID NO: 16.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201161568590P | 2011-12-08 | 2011-12-08 | |
| PCT/US2012/068606 WO2013086441A2 (en) | 2011-12-08 | 2012-12-07 | Oligonucleotide analogues targeting human lmna |
| EP12805882.3A EP2788487B1 (en) | 2011-12-08 | 2012-12-07 | Oligonucleotide analogues targeting human lmna |
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| HRP20181022T1 true HRP20181022T1 (hr) | 2018-08-24 |
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| HRP20181022TT HRP20181022T1 (hr) | 2011-12-08 | 2018-07-03 | Analozi oligonukleotida koji ciljaju ljudski lmna |
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| US (7) | US9066967B2 (hr) |
| EP (3) | EP2788487B1 (hr) |
| JP (7) | JP6132848B2 (hr) |
| CY (1) | CY1120495T1 (hr) |
| DK (1) | DK2788487T3 (hr) |
| ES (2) | ES2674929T3 (hr) |
| HR (1) | HRP20181022T1 (hr) |
| HU (1) | HUE038369T2 (hr) |
| LT (1) | LT2788487T (hr) |
| PL (1) | PL2788487T3 (hr) |
| PT (1) | PT2788487T (hr) |
| RS (1) | RS57467B1 (hr) |
| SI (1) | SI2788487T1 (hr) |
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