Biomarkers of METAP2 inhibitors and applications thereof
Inventors
Cornelius, Peter • Shanahan, James
Assignees
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Publication Number
US-12419846-B2
Publication Date
2025-09-23
Expiration Date
Abstract
The present disclosure relates to modified or polymer conjugated MetAP2 inhibitors. The present disclosure also relates to methods of treating, or ameliorating at least one symptom of, metabolic dysfunction associated with a treatment in a subject having cancer. The present disclosure also relates to methods of treating, or ameliorating at least one symptom of, cancer comprising administering a combination of a polymer conjugated MetAP2 inhibitors and at least one second agent.
Core Innovation
The disclosure provides a method for treating, or ameliorating at least one symptom of, HER2+ breast cancer or triple negative breast cancer in a subject in need thereof. The method comprises administering a therapeutically effective amount of a polymer-conjugated MetAP2 inhibitor compound of the Formula, or a pharmaceutically acceptable salt thereof, in combination with capivasertib (AZD5363). The disclosed compounds encompass fumagillin- and fumagillol-based conjugates comprising specified polymer, peptide, and linker components.
Cleavage of self-immolating linkers releases the inhibitor as a carbamate derivative, potentially reducing cellular efflux and improving pharmacokinetic profiles. The conjugates address limitations associated with known fumagillin derivatives, specifically TNP-470 neurotoxicity, instability, and short half-life, by providing reduced toxicity, improved water solubility, and extended serum half-life. Furthermore, administering the Formula compound attenuates capivasertib-induced hyperglycemia, hyperinsulinemia, and insulin resistance while reducing mammary tumor growth.
Claims Coverage
The claim information identifies one independent claim covering a combination cancer therapy, accompanied by dependent refinements encompassing four inventive features.
Combination treatment of specified breast cancers
The independent claim covers treating cancer or ameliorating at least one symptom of HER2+ breast cancer or triple negative breast cancer in a subject by administering a therapeutically effective amount of a compound of the claimed Formula, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of capivasertib (AZD5363).
Formula compound parameters
The claimed compound is defined by the Formula with x in the range of 1 to about 450, y in the range of 1 to about 30, and n in the range of 1 to about 100, or a pharmaceutically acceptable salt thereof.
Pretreatment to attenuate capivasertib-induced hyperglycemia
Dependent claims specify that the subject receives the Formula compound prior to capivasertib administration, wherein administration of the compound attenuates capivasertib-induced hyperglycemia.
Administration timing and order
Dependent claims specify that the Formula compound and capivasertib are administered sequentially or in a substantially simultaneous manner.
The independent claim establishes a combination therapy using a Formula compound and capivasertib for HER2+ or triple negative breast cancer, while dependent claims further define compound substituents, administration order, and pretreatment for attenuating capivasertib-induced hyperglycemia.
Stated Advantages
Pretreatment with the Formula compound attenuates capivasertib-induced hyperglycemia.
The conjugate design is described as potentially reducing cellular efflux and improving efficacy and pharmacokinetic profiles.
The claimed method treats HER2+ breast cancer or triple negative breast cancer, or ameliorates at least one symptom of either cancer, with combination treatments showing reduced tumor growth relative to vehicle.
The conjugates provide reduced toxicity, addressing TNP-470 neurotoxicity, compared with known fumagillin derivatives.
The conjugates exhibit improved water solubility, stability, and longer serum half-life compared with known fumagillin derivatives.
Documented Applications
Treatment or amelioration of at least one symptom of HER2+ breast cancer or triple negative breast cancer in a subject in need thereof using a Formula compound in combination with capivasertib (AZD5363).
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