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Publication Number
US-10232049-B2
Publication Date
2019-03-19
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 binding moiety-drug conjugates (SDC-TRAPs) comprising a binding moiety and an effector moiety, wherein the binding moiety binds to Hsp90 and the effector moiety is a cytotoxic agent selected from flavopiridol, lapatinib, axitinib, vemurafenib, imatinib, staurosporine, panobinostat, carfilzomib, INCB024360, and methyl tryptophan, or fragment(s) thereof. The binding moiety and the effector moiety are covalently attached, and the covalent attachment can be mediated by a linker, including cleavable linker formats.
The disclosure presents multiple SDC-TRAP examples and structural variants with characterization data, including NMR and ESMS or ESMS mass characterization. It also describes Hsp90-binding moieties such as Hsp90 ligands or prodrugs of Hsp90 ligands, and Hsp90 inhibitors selected from geldanamycins, macbecins, tripterins, tanespimycins, and radicicols.
The document further reports in vitro HER2 degradation activity, Hsp90α binding results, mouse plasma stability, and tissue distribution data for selected SDC-TRAP compounds. It describes selective intracellular trapping or retention in cells overexpressing the intracellular target, increased intracellular effector levels, and rapid clearance from normal tissues with relatively persistent tumor exposure in a tissue distribution study.
Claims Coverage
The consolidated claim coverage centers on one independent SDC-TRAP claim. The inventive core is an Hsp90-binding moiety covalently attached to a specified cytotoxic effector moiety, with dependent refinements directed to the Hsp90-binding moiety format, linker-mediated attachment and enzymatically cleavable linkers, specific Hsp90 inhibitor selections, and molecular weight thresholds.
Hsp90-binding moiety covalently attached to cytotoxic effector
A binding moiety-drug conjugate (SDC-TRAP) comprising a binding moiety and an effector moiety, wherein the binding moiety binds to Hsp90, the effector moiety is a cytotoxic agent selected from flavopiridol, lapatinib, axitinib, vemurafenib, imatinib, staurosporine, panobinostat, carfilzomib, INCB024360 and methyl tryptophan or (a) fragment(s) thereof, and wherein the binding moiety and the effector moiety are covalently attached.
Hsp90 ligand or prodrug binding moiety
The SDC-TRAP wherein the binding moiety is an Hsp90 ligand or a prodrug of the Hsp90 ligand.
Linker-mediated covalent attachment
The SDC-TRAP wherein the binding moiety and the effector moiety are covalently attached via a linker.
Enzymatically cleavable linker
The SDC-TRAP wherein the cleavable linker is an enzymatically cleavable linker.
Hsp90 inhibitor selection for the binding moiety
The SDC-TRAP wherein the Hsp90 inhibitor is selected from geldanamycins, macbecins, tripterins, tanespimycins, and radicicols.
Molecular weight limit for the conjugate
The SDC-TRAP having a molecular weight less than about 1600 Daltons, 1200 Daltons, 800 Daltons, 600 Daltons, or 400 Daltons.
Overall, the claim set covers an SDC-TRAP architecture in which an Hsp90-binding moiety is covalently attached to a listed cytotoxic effector moiety or fragment, with dependent claims narrowing the binding moiety to an Hsp90 ligand or prodrug, specifying linker and enzymatically cleavable linker options, identifying Hsp90 inhibitor subclasses, and imposing molecular weight thresholds.
Stated Advantages
Lung accumulation after oral delivery.
Reduced toxicity/irritation.
Enables delivery of otherwise unsuitable/toxic agents via covalent attachment using cleavable or enzymatically cleavable linkers.
Enables selective intracellular release of the effector.
Selective retention in cells overexpressing the intracellular target of the binding moiety.
Increased intracellular effector levels.
Potentially reduced systemic toxicity.
Rapid clearance from normal tissues.
Documented Applications
Characterization and example embodiments of Hsp90-targeting SDC-TRAP conjugates, including ESMS and structural data for multiple small molecules.
Evaluation of HER2 degradation associated with Hsp90-targeting SDC-TRAP conjugates.
Assessment of Hsp90 binding, IC50 data, cytotoxicity, plasma stability, degradation fragment release, and tissue distribution for SDC-TRAP conjugates.
Xenograft efficacy setup for SDC-TRAP-0063.
Treatment methods for cancer.
Treatment methods for actinic keratosis.
Treatment methods for asthma.
Treatment methods for chronic bronchitis.
Treatment methods for COPD.
Treatment methods for skin cancer.
Therapeutic use of SDC-TRAP targeted therapeutics as pharmacological effector-binding moiety conjugates directed into target cells.
Diagnostic and imaging use cases are referenced for the SDC-TRAP targeted therapeutics.
In vitro HER2 degradation activity assessment for multiple SDC-TRAP compounds.
Mouse plasma stability and tissue distribution studies for selected SDC-TRAP compounds.
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