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US 2024/0174708 A1Published application
Compounds for targeted protein degradation
AssigneeAmbagon Therapeutics Inc.
InventorsNancy PRYER, Christian OTTMANN, Steven RICHARDS
Life of this patent
Estimating the term…
Abstract
Provided are compounds, including compositions comprising the same, which function to recruit various target proteins (e.g., client proteins of 14-3-3 proteins) to an E3 ubiquitin ligase enzyme for ubiquitination and subsequent degradation, and methods of using the same.
Claims20
A method for inducing ubiquitylation and/or degradation of a client protein in a cell, the method comprising:
- contacting the cell with a proteolytic modulator comprising an E3 ubiquitin ligase binding moiety, wherein the proteolytic modulator binds to a protein-protein complex of a 14-3-3 protein and a client protein, thereby inducing ubiquitylation and/or degradation of the client protein in the cell;
- or
- a method for treating or preventing a disease, disorder, or condition in a subject in need thereof wherein dysregulated activity of a client protein is responsible for the disease, disorder, or condition, the method comprising:
- administering to the subject a proteolytic modulator comprising an E3 ubiquitin ligase binding moiety, wherein the proteolytic modulator binds to a protein-protein complex of a 14-3-3 protein and a client protein, thereby inducing ubiquitylation and/or degradation of the client protein;
- or
- a method of treating or preventing a condition conducive to treatment or prevention by degrading a client protein in subject comprising administering to the subject a proteolytic modulator comprising an E3 ubiquitin ligase binding moiety, wherein the proteolytic modulator binds to a protein-protein complex of a 14-3-3 protein and a client protein, thereby inducing ubiquitylation and/or degradation of the client protein;
- wherein the proteolytic modulator is a bifunctional compound having a formula of G-L-BM, wherein G is a fusicoccin moiety or a derivative thereof that binds to the protein-protein complex of the 14-3-3 protein and the client protein, L is a linker, and BM is the E3 ubiquitin ligase binding moiety;
- or wherein G comprises a fusicoccin A (FCA) moiety or a derivative thereof.
5 more elements
A compound of Formula (I), or a pharmaceutically acceptable salt thereof:
- wherein:
- R1 and R2 are each independently hydrogen or L-BM;
- L is a linker;
- and BM is an E3 ubiquitin ligase binding moiety;
- R3a and R3b are each independently hydrogen or optionally substituted C1-C6 alkyl, or R3a and R3b form an oxo;
- R4a and R4b are each independently hydrogen or optionally substituted C1-C6 alkyl;
- R5 is hydrogen or —C(O)R8;
- R6 and R7 are each independently hydrogen, —OH, or optionally substituted C1-C6 alkyl;
- R8 is hydrogen or optionally substituted C1-C6 alkyl;
- X and Y are each independently a bond, —O—, —CH2—, or —NR—;
- wherein R is hydrogen or optionally substituted C1-C6 alkyl;
- m and n are each independently 0, 1, 2, 3, 4, 5, or 6;
- each represents a single bond or a double bond;
- and
- provided that R1 and R2 are not both hydrogen.
12 more elements
A compound of Formula (II), or a pharmaceutically acceptable salt thereof:
- wherein:
- R11 and R12 are each independently hydrogen or L-BM;
- L is a linker;
- and BM is an E3 ubiquitin ligase binding moiety;
- R13a and R13b are each independently hydrogen or optionally substituted C1-C6 alkyl, or R13a and R13b form an oxo;
- R14 and R15 are each independently hydrogen, —OH, or optionally substituted C1-C6 alkyl;
- X and Y are each independently a bond, —O—, —CH2—, or —NR—;
- wherein R is hydrogen or optionally substituted C1-C6 alkyl;
- m is 0, 1, 2, 3, 4, 5, or 6;
- each represents a single bond or a double bond;
- and
- provided that R11 and R12 are not both hydrogen.
9 more elements
Dependencies are inferred from the claim text.