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US 2026/0306459 A1Published application
Inhibitors of nsun1- and nsun2-mediated active structures
OwnerJason X. CHENG, Rick L. STEVENSinventors
Life of this patent
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Abstract
Provided herein are methods and compositions for the inhibition of NSUN1 and/or NSUN2 interactions with certain binding partners, such as bromodomain-containing protein 4 (BRD4) and elongating RNA polymerase II (eRNAPII). Also provided herein are methods and compositions for treatment of drug resistant cancer, particularly venetoclax and/or 5-AZA resistant cancer.
Claims102
A method of treating a disease in an individual, the method comprising the step of administering to the individual a therapeutically effective amount of any one or more of an inhibitor of NSUN1 and/or NSUN2 interactions with Active Chromatin Site (ACS) associated proteins and/or complexes (NSUN1/2-ACS inhibitor).
A method of overcoming and/or preventing cancer cell drug resistance to venetoclax-based and/or 5-azacytidine-based therapies comprising, contacting the cancer cell with one or more inhibitors of NSUN1 and/or NSUN2 interactions with Active Chromatin Site (ACS) associated proteins and/or complexes (NSUN1/2-ACS inhibitor).
A method of treating refractory cancer comprising, treatment with an NSUN1 and/or NSUN2 protein-protein interaction inhibitor with a NSUN1/2-ACS inhibitor.
A composition comprising NSUN2-11, NSUN2-37, NSUN1-9, NSUN1-10, NSUN1-11, NSUN1-17, NSUN1-17.13, NSUN1-17.16, NSUN1-24, NSUN1-25, NSUN1-27, NSUN1-30, NSUN1-31, NSUN1-54, NSUN1-64, NSUN1-67, NSUN1-73, NSUN1-74, NSUN2-3, NSUN2-10, NSUN2-17, NSUN2-18, NSUN2-19, NSUN2-20, NSUN2-21, NSUN2-35, NSUN2-38, NSUN2-39, NSUN2-64, NSUN2-98, and/or a derivative thereof, and a pharmaceutically acceptable excipient.
A composition comprising a compound of formula I
- wherein:
- R1 is CH2, NH, O, or S;
- R2 is CH or N;
- R3 is CH2, NH, O, or S;
- R4 is NH or CH2;
- R5 is N or CH;
- R6 is N or CH;
- R7 is CH2, NH, O, or S;
- R8 is H, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide;
- R9 is H, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide;
- R10 is H, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide;
- and
- R11 is H, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide;
- or an enantiomer, diastereomer, racemic mixture, or salt thereof.
11 more elements
A composition comprising a compound of formula IV:
- wherein:
- R44 is O, S, NH, or CH2
- R45 is CH2, NH, O, or S
- R46 is CH or N;
- R47 is NH, N-alkyl, O, or S;
- R48 is CH2 or NH;
- R49 is CH or N;
- R50 is CH2, NH, O, or S;
- R51 is H, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide;
- R52 is H, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide;
- R53 is H, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide;
- R54 is H, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide;
- R55 is H, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide;
- R56 is H, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide;
- R57 is H, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide;
- and
- R58 is H, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide;
- or an enantiomer, diastereomer, racemic mixture, or salt thereof.
15 more elements
A composition comprising a compound of formula V:
- wherein:
- R59 is CH or N;
- R60 is CN2, NH, O, or S;
- R61 is O or S;
- R62 is CH2, NH, O, or S;
- R63 is H, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide;
- R64 is H, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide;
- R65 is H, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide;
- R66 is H, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide;
- R67 is H, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide;
- R68 is H, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide;
- R69 is H, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide;
- R70 is H, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide;
- R71 is H, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide;
- R72 is H, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide;
- R73 is H, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide;
- R74 is H, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide;
- R75 is H, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide;
- or an enantiomer, diastereomer, racemic mixture, or salt thereof.
16 more elements
Dependencies are inferred from the claim text.