US2022315927A1PendingUtilityA1

Modulators of yap1 expression

Assignee: IONIS PHARMACEUTICALS INCPriority: Jan 31, 2019Filed: Nov 16, 2021Published: Oct 6, 2022
Est. expiryJan 31, 2039(~12.5 yrs left)· nominal 20-yr term from priority
A61K 31/7088C12N 2310/346A61K 9/0012A61K 45/06C12N 2310/3231C12N 2320/31C12N 15/11A61P 35/00C12N 15/113C12N 2310/315A61K 31/7125C12N 15/1135A61K 31/712C12N 2320/11C12N 2310/321C12N 2310/341A61K 45/00A61K 31/44C12N 2310/11C12N 2310/3341
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Claims

Abstract

The present embodiments provide methods, compounds, and compositions useful for inhibiting YAP1 expression, which may be useful for treating, preventing, or ameliorating a cancer associated with YAP1.

Claims

exact text as granted — not AI-modified
1 .- 8 . (canceled) 
     
     
         9 . A compound comprising a modified oligonucleotide consisting of 8 to 80 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases of a nucleobase sequence selected from the group consisting of SEQ ID NOs: 810, 1404, 2868, 2864, 286-5-1-494-1101, 2812, 1200, and 2863. 
     
     
         10 .- 16 . (canceled) 
     
     
         17 . A compound comprising a modified oligonucleotide having a nucleobase sequence consisting of a nucleobase sequence selected from the group consisting of SEQ ID NOs: 810, 1404, 2868, 2864, 286-1-404, 1101, 2812, 1200, or 2863. 
     
     
         18 . The compound of  claim 17 , wherein at least one internucleoside linkage of the modified oligonucleotide is a modified internucleoside linkage, at least one sugar of the modified oligonucleotide is a modified sugar, or at least one nucleobase of the modified oligonucleotide is a modified nucleobase. 
     
     
         19 . The compound of  claim 18 , wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         20 . The compound of  claim 18 , wherein the modified sugar is a bicyclic sugar. 
     
     
         21 . The compound of  claim 20 , wherein the bicyclic sugar is selected from the group consisting of: 4′-(CH 2 )—O—2′ (LNA); 4′-(CH 2 ) 2 —O—2′ (ENA); and 4′-CH(CH 3 )—O—2′ (cEt). 
     
     
         22 . The compound of  claim 18 , wherein the modified sugar is 2′-O-methoxyethyl. 
     
     
         23 . The compound of  claim 18 , wherein the modified nucleobase is 5-methylcytosine. 
     
     
         24 . The compound of  claim 17 , wherein the modified oligonucleotide has:
 a gap segment consisting of linked 2′-deoxynucleosides;   a 5′ wing segment consisting of linked nucleosides; and   a 3′ wing segment consisting of linked nucleosides;   wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.   
     
     
         25 .- 37 . (canceled) 
     
     
         38 . A compound consisting of a pharmaceutically acceptable salt of the compound of  claim 17 . 
     
     
         39 . The compound of  claim 38 , wherein the pharmaceutically acceptable salt is a sodium salt. 
     
     
         40 . The compound of  claim 38 , wherein the pharmaceutically acceptable salt is a potassium salt. 
     
     
         41 . (canceled) 
     
     
         42 . (canceled) 
     
     
         43 . (canceled) 
     
     
         44 . A composition comprising the compound of  claim 17  and a pharmaceutically acceptable diluent or carrier. 
     
     
         45 . A composition comprising the compound of  claim 17  and water. 
     
     
         46 . (canceled) 
     
     
         47 . A combination comprising the compound of  claim 17  and a secondary agent. 
     
     
         48 . The combination of  claim 47 , wherein the secondary agent is a CDK4/6 inhibitor. 
     
     
         49 . (canceled) 
     
     
         50 . The combination of  claim 47 , wherein the secondary agent is an EGFR inhibitor. 
     
     
         51 . (canceled) 
     
     
         52 . The combination of  claim 47 , wherein the secondary agent is a kinase inhibitor. 
     
     
         53 .- 64 . (canceled) 
     
     
         65 . A method of inhibiting expression of YAP1 in a cell comprising contacting the cell with a compound of  claim 17 , thereby inhibiting expression of YAP1 in the cell. 
     
     
         66 . The method of  claim 65 , wherein the cell a cancer cell. 
     
     
         67 .- 99 . (canceled)

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