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Publication Number
US-10117944-B2
Publication Date
2018-11-06
Expiration Date
Abstract
The present invention provides pharmacological compounds including an effector moiety conjugated to a binding moiety that directs the effector moiety to a biological target of interest. Likewise, the present invention provides compositions, kits, and methods (e.g., therapeutic, diagnostic, and imaging) including the compounds. The compounds can be described as a protein interacting binding moiety-drug conjugate (SDC-TRAP) compounds, which include a protein interacting binding moiety and an effector moiety. For example, in certain embodiments directed to treating cancer, the SDC-TRAP can include an Hsp90 inhibitor conjugated to a cytotoxic agent as the effector moiety.
Core Innovation
The invention relates to a binding moiety-drug conjugate (SDC-TRAP) comprising a binding moiety and an effector moiety, wherein the binding moiety binds to HSP90 and the binding moiety and the effector moiety are covalently attached. The effector moiety is a proteasome inhibitor selected from bortezomib, ixazomib, and delanzomib, or a fragment thereof. The disclosed set includes named SDC-TRAP members such as SDC-TRAP-0236 through SDC-TRAP-0252.
The disclosed SDC-TRAP platform includes Hsp90-targeting moieties, Hsp90 ligand or HSP90 inhibitor binding moieties, and linker options such as direct attachment, spacers, reactive functionalities, cleavable linkers, and enzymatically cleavable linkers. The disclosure also describes sterically hindered boronate ester linkage concepts for HSP90 inhibitor-bortezomib conjugates, an alternative dative N-stabilized boronate concept, and carbamate linkage.
The disclosure further describes intracellular trapping, selective retention in HSP90-overexpressing target cells, target protein degradation, and glucocorticoid receptor (GR)/Hsp90 client degradation in inflammation. The document also includes example conjugates with illustrative chemical characterization and biological and biophysical data including mouse plasma stability, HER2 degradation potency in BT-474 cells, tissue distribution and metabolism measurements for ganetespib in mice, and cytotoxicity and anti-tumor efficacy assessments.
Claims Coverage
Two independent claim scopes are present. Across these claims, the inventive features cover an HSP90-binding moiety-drug conjugate with a proteasome-inhibitor effector and a defined set of named SDC-TRAP variants or pharmaceutically acceptable salts. In total, the coverage centers on four inventive features.
Hsp90-binding covalently attached proteasome inhibitor conjugate
An SDC-TRAP comprising a binding moiety and an effector moiety, wherein the effector moiety is a proteasome inhibitor selected from bortezomib, ixazomib, and delanzomib, or fragment thereof, the binding moiety binds to HSP90, and the binding moiety and the effector moiety are covalently attached.
Hsp90 ligand or prodrug binding moiety
The binding moiety is an Hsp90 ligand or a prodrug of the Hsp90 ligand.
Cleavable linker in the conjugate
The linker includes a cleavable linker.
Named SDC-TRAP variants and pharmaceutically acceptable salts
An SDC-TRAP or its pharmaceutically acceptable salt, wherein the SDC-TRAP is selected from the group consisting of SDC-TRAP-0236, SDC-TRAP-0237, SDC-TRAP-0238, SDC-TRAP-0239, SDC-TRAP-0240, SDC-TRAP-0241, SDC-TRAP-0242, SDC-TRAP-0243, SDC-TRAP-0244, SDC-TRAP-0245, SDC-TRAP-0246, SDC-TRAP-0247, SDC-TRAP-0248, SDC-TRAP-0249, SDC-TRAP-0250, SDC-TRAP-0251, and SDC-TRAP-0252.
Overall, claim coverage centers on an HSP90-binding SDC-TRAP conjugate with a covalently attached proteasome inhibitor effector, with dependent refinements for Hsp90 ligand or prodrug binding moieties, cleavable linkers, and specific named SDC-TRAP variants or salts.
Stated Advantages
Reduced systemic toxicity.
Improved efficacy via selective intracellular release and trapping of an Hsp90-targeted effector.
Selective retention in target cells, including HSP90-overexpressing cells, by exploiting intracellular overexpression of the binding target.
Increased intracellular effector levels.
Preferential cleavage and release where cleavable linkers are used.
Clearance from non-target cells.
Reduced toxicity with increased efficacy.
Safety/clearance advantages versus antibody-drug conjugates.
Documented Applications
Mouse plasma stability measurements as percent remaining at 1 h.
HER2 degradation potency in BT-474 cells, including IC50 values.
Tissue distribution and metabolism measurements for ganetespib across tissues and tumor in mice.
Cytotoxicity and anti-tumor efficacy assessment using in vitro and in vivo evaluations [procedural detail omitted for safety].
Treatment methods across multiple cancer types using the disclosed SDC-TRAPs for Hsp90-targeted effector intracellular trapping.
Therapeutic uses for the disclosed SDC-TRAPs via pharmaceutical compositions.
Diagnostic uses as described for the disclosed SDC-TRAPs.
Imaging uses as described for the disclosed SDC-TRAPs.
Therapeutic, diagnostic, and imaging kits are described in connection with the disclosed SDC-TRAPs.
Inflammation via Hsp90 client protein glucocorticoid receptor (GR) degradation.
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