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.
Claims22
(canceled)
A method for reducing ubiquitination and inducing accumulation of the NRF2 by exposing a target cell to conditions or compounds that induce conditions that result in covalent modification of Kelch-like ECH-associated protein 1 (KEAP1).
(canceled)
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) zamino, 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 recrutier 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) zamino, 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 a subject for pulmonary fibrosis, acute lung injury, cancer, a neurodegenerative disorder, a chronic inflammatory disease, diabetes, an autoimmune disease, or aging comprising administering an activator of Nrf2 dependent gene expression to the subject, wherein the activator of Nrf2 dependent gene expression is a compound of Formula I or Formula II.
12-13. (canceled)
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 a direct bond, N, or O.
Dependencies are inferred from the claim text.