Compositions and methods for activating nrf2-dependent gene expression
AssigneeThe University of Chicago
InventorsRaymond MOELLERING, John COUKOS, Gihoon LEE, Jae Won CHANG, Gokhan MUTLU
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Abstract
Embodiments are directed to a series of novel small molecule activators of NRF2 dependent gene expression that are evaluated in an effort to develop therapeutic methods against diseases with deregulated KEAP1-NRF2 signaling.
Claims17
A method for activating Nrf2 dependent transcription by inhibiting phosphoglycerate kinase 1 (PGK1) with a compound having a general formula of Formula I or Formula II.
A method for reducing ubiquitination and inducing accumulation of the NRF2 by exposing a target cell to conditions, compounds or compounds that induce conditions that result in covalent modification of Kelch-like ECH-associated protein 1 (KEAP1).
A phosphoglycerate kinase 1 inhibitor having a general formula of:
- where R1, R2, R3, R4, and R5 are independently selected from hydrogen, halo, nitro, mercapto, cyano, azido, silyl, hydroxy, amino, formyl, carboxy, oxo, carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, cycloalkyl, heterocyclyl, aryl, and/or heteroaryl;
- x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20;
- and
- Y is N or O,
- wherein R1 and R2 are not chlorine when x is 1, R3 is hydrogen, Y is O, R4 is tert-butyl, and R5 is hydrogen.
A phosphoglycerate kinase 1 inhibitor/ubiquitin recruiter having a general formula of:
- where where R1, R2 and R3 are independently selected from hydrogen, halo, nitro, mercapto, cyano, azido, silyl, hydroxy, amino, formyl, carboxy, oxo, carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, cycloalkyl, heterocyclyl, aryl, and/or heteroaryl;
- x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20;
- x′ is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20;
- W is bond, amide, or diol;
- V is N or O;
- and
- Z is a recruiter molecule.
A method for activating Nrf2 dependent gene expression by inhibiting phosphoglycerate kinase 1 (PGK1) with a compound of Formula I or Formula II.
A method of treating pulmonary fibrosis comprising administering an activator of Nrf2 dependent gene expression to a subject having pulmonary fibrosis, wherein the activator of Nrf2 dependent gene expression is a compound of Formula I or Formula II.
A method of treating acute lung injury comprising administering an activator of Nrf2 dependent gene expression to a subject having acute lung injury, wherein the activator of Nrf2 dependent gene expression is a compound of Formula I or Formula II.
A method of enhancing an immune response comprising administering an activator of Nrf2 dependent gene expression to a subject, wherein the activator of Nrf2 dependent gene expression is a compound of Formula I or Formula II.
A phosphoglycerate kinase 1 inhibitors having a general formula of:
- where R1, R2, R3, R4, and R5 are independently selected from hydrogen, halo, nitro, mercapto, cyano, azido, silyl, hydroxy, amino, formyl, carboxy, oxo, carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, cycloalkyl, heterocyclyl, aryl, and/or heteroaryl;
- x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20;
- and
- Y is a direct bond, N, or O.
Dependencies are inferred from the claim text.