Cyclin-dependent kinase degraders and methods of use
AssigneeDana-Farber Cancer Institute, Inc.
InventorsNathanael S. Gray, John Hatcher
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Abstract
The present application provides compounds of Formula (Ia), or an enantiomer, diastereomer, stereoisomer, or pharmaceutically acceptable salt thereof, which act as protein degradation inducing moieties for one or more of cyclin-dependent kinase 8 (CDK8) and cyclin-dependent kinase 19 (CDK19). The present application also relates to methods for the targeted degradation of CDK8 and/or CDK19 through the use of the compounds that link a ubiquitin ligase-binding moiety to a ligand that is capable of binding to CDK8 and/or CDK19 which can be utilized in the treatment of disorders modulated by CDK8 and/or CDK19.
Claims13
A compound or a pharmaceutically acceptable salt of Formula X:
- wherein:
- the Targeting Ligand is of the following structure:
- wherein the Targeting Ligand is bonded to the Linker via the
- the Linker is a group that covalently binds to the Targeting Ligand and the Degron and is of Formula L0:
- wherein
- p1 is an integer selected from 4 to 12;
- p2 is 0;
- p3 is 2;
- each W is O;
- Z3 is C (O);
- and
- Q is a bond,
- wherein the Linker is covalently bonded to the Degron via the
- next to Q, and covalently bonded to the Targeting Ligand via the
- next to Z3;
- and
- the Degron is of Formula D1a′:
- wherein:
- Y is NH;
- R13 is H or C1-C3 alkyl;
- and
- wherein the Degron is covalently bonded to the Linker via
A compound, having any one of structures:
- or a pharmaceutically acceptable salt thereof.
The compound having the following structure:
- or a pharmaceutically acceptable salt thereof.
The compound having the following structure:
- or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.