Degraders of WEE1 kinase
Inventors
Gray, Nathanael S. • Scott, David • Li, Zhengnian • Pinch, Benika J. • Olson, Calla • Fischer, Eric S. • NOWAK, Radoslaw P. • Donovan, Katherine A.
Assignees
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Publication Number
US-12318452-B2
Publication Date
2025-06-03
Expiration Date
Abstract
Disclosed are bifunctional compounds (degraders) that target Wee1 tyrosine kinase for degradation. Also disclosed are pharmaceutical compositions containing the degraders and methods of using the compounds to treat disease.
Core Innovation
The invention relates to a compound having a structure represented by formula I, comprising a Wee1 kinase targeting ligand, a degron, and a linker. The targeting ligand is a moiety that binds Wee1 kinase, and the degron is defined with Y' as a bond, N, O or C, and Z as a C5-C6 carbocyclic group or a C5-C6 heterocyclic group.
The linker is an alkylene chain or a polyethylene glycol chain, and it may be interrupted and/or terminate at either or both termini with specified groups, including O, S, N(R'), C≡C, C(O), C(O)O, OC(O), and OC(O)O, together with other heteroatom-containing linkages and ring-containing options described in the claims. The disclosed embodiments include linker architectures and degron variants, and the compound scope includes pharmaceutically acceptable salts and stereoisomers.
The subject matter further presents bifunctional compounds in which the Wee1-targeting ligand is connected through the defined linker to the degron portion, including cereblon-binding degron units and VHL-binding degron units described in the partial content. The disclosure also references structural embodiments associated with the ubiquitin-proteasome pathway and representative full architectures of the bifunctional compounds.
Claims Coverage
The independent claim coverage centers on a formula I compound defined by a Wee1 kinase targeting ligand, a specified degron framework, and a specified linker architecture. The claim set uses four inventive features, with dependent claims refining linker constraints and therapeutic use, including combination therapy in some items.
Wee1 kinase targeting ligand moiety
The targeting ligand is a moiety that binds Wee1 kinase and is represented by a structure selected from depicted targeting-ligand structures.
Defined degron with Y' and Z
The degron includes Y' as a bond, N, O or C, and Z as a C5-C6 carbocyclic group or a C5-C6 heterocyclic group.
Alkylene or polyethylene glycol linker with specified interruptions and terminations
The linker is an alkylene chain or a polyethylene glycol chain that may be interrupted and/or terminate at either or both termini with selected groups and related heteroatom-containing or ring-containing linkages, with R' defined as H or C1-C6 alkyl.
Pharmaceutically acceptable salts and stereoisomers
The compound scope includes pharmaceutically acceptable salts and stereoisomers thereof.
Overall, the claims define a formula I Wee1 kinase-binding bifunctional compound combining a targeting ligand, a degron defined by Y' and Z, and an alkylene or PEG linker with specified interruptions and terminations, with salts and stereoisomers included.
Stated Advantages
Lower effective intracellular concentrations.
Improved pharmacodynamics.
Potential reduced resistance.
Enables combination therapy with additional anticancer agents, including a PARP inhibitor and CHK1 inhibitors.
Documented Applications
Treating diseases mediated by aberrant Wee1 activity, including cell proliferative diseases and disorders and cancer.
Combination therapy for cancer using a formula I compound together with additional anticancer agents, including a PARP inhibitor such as Olaparib and CHK1 inhibitors such as MK-8776 and SCH900444/SCH1396195.
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