Cyclin-dependent kinase degraders and methods of use

Inventors

Gray, Nathanael S. • Hatcher, John

Assignees

Dana Farber Cancer Institute Inc

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.

Core Innovation

The patent describes compounds or pharmaceutically acceptable salts of Formula X in which a Targeting Ligand is bonded to a Linker, and the Linker covalently binds to the Targeting Ligand and a Degron. The Linker is of Formula L0 with constraints including p1 being an integer selected from 4 to 12, p2 being 0, p3 being 2, each W being O, Z3 being C(O), and Q being a bond, and the Linker is covalently bonded to the Degron via the position next to Q and to the Targeting Ligand via the position next to Z3.

The Degron is of Formula D1a′, where Y is NH and R13 is H or C1-C3 alkyl, and the Degron is covalently bonded to the Linker via a defined connection. The document describes bifunctional CDK8/CDK19-targeting compounds, PROTAC-style ternary-complex formation, and an embodiment where the E3 ubiquitin ligase is cereblon. It also refers to stereochemical and isomeric coverage, including glutarimide and S-valerolactam degron derivatives.

The document further provides pharmaceutical and chemical scope for these bifunctional compounds, including pharmaceutically acceptable prodrugs and pharmaceutically acceptable zwitterionic forms. It also ties the compounds to pharmaceutical compositions, kits, and medicament concepts.

Claims Coverage

The consolidated claim coverage identifies multiple independent claim scopes centered on structurally defined compounds or pharmaceutically acceptable salts. The main inventive features are the Formula X Targeting Ligand–Linker–Degron architecture with Formula L0 and Formula D1a′ constraints, additional structure-defined compound claims, and dependent coverage that adds pharmaceutical compositions and therapeutic methods.

Overall, the claim coverage is centered on a covalently connected Targeting Ligand–Linker–Degron architecture with defined Formula L0 and Formula D1a′ constraints, together with separate claims to structure-defined compounds or compounds represented by one of multiple structural depictions. Dependent claims further narrow specific substituent and parameter choices and add pharmaceutical composition and therapeutic-use coverage, including treatment of acute myeloid leukemia and lymphoma.

Stated Advantages

Documented Applications