E-selectin antagonist compounds, compositions, and methods of use
Inventors
Magnani, John L. • Sarkar, Arun K. • Baek, Myung-Gi • Anderson, III, Frank E. • Li, Yanhong
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11332491-B2
Publication Date
2022-05-17
Expiration Date
Abstract
Methods and compositions using E-selectin antagonists are provided for the treatment and prevention of diseases and disorders treatable by inhibiting binding of E-selectin to an E-selectin ligand. Described herein are E-selectin antagonists including, for example, glycomimetic compounds, antibodies, aptamers and peptides that are useful in methods for treatment of cancers, and treatment and prevention of metastasis, inhibiting infiltration of the cancer cells into bone marrow, reducing or inhibiting adhesion of the cancer cells to endothelial cells including cells in bone marrow, and inhibiting thrombus formation.
Core Innovation
The patent describes E-selectin antagonist agents and pharmaceutical compositions comprising compounds having formula (I), including pharmaceutically acceptable salts, isomers, tautomers, hydrates, solvates, metabolites, prodrugs, and related derivatives. The compounds include a linker-non-glycomimetic moiety in which the linker is —C(=O)NH(CH2)1-4NHC(=O)—, and the non-glycomimetic moiety comprises polyethylene glycol.
The patent states that the agents are used to treat and/or prevent diseases associated with E-selectin ligand binding, with an emphasis on cancer progression and metastasis. The document further describes inhibiting tumor infiltration into bone marrow and reducing tumor cell adhesion to endothelial cells, including within bone marrow.
The compounds and corresponding pharmaceutical compositions are stated to be used for treating and/or preventing diseases by inhibiting E-selectin-ligand interactions, including E-selectin and sLea/sLex ligands. The patent also describes therapeutic and adjunct use in combination with chemotherapy and radiotherapy.
Claims Coverage
The independent claims cover four inventive features centered on administering a formula (I) compound with a polyethylene glycol-containing linker-non-glycomimetic moiety, applied to hematopoietic stem cell chemosensitivity/radiosensitivity reduction or cancer treatment selected by E-selectin activity or E-selectin binding ligand expression.
Reducing chemosensitivity or radiosensitivity of hematopoietic stem cells
A method for reducing chemosensitivity or radiosensitivity of hematopoietic stem cells in a subject by administering a pharmaceutical composition comprising a compound having formula (I) with R1–R8 defined and pharmaceutically acceptable salt/isomer/tautomer/hydrate/solvate, where R2 is a linker-non-glycomimetic moiety with linker —C(=O)NH(CH2)1-4NHC(=O)— and the non-glycomimetic moiety comprises polyethylene glycol.
Treating cancer in subjects with highly active E-selectin
A method for treating cancer in a subject expressing a highly active E-selectin as determined by the genetic polymorphism for E-selectin of S128R by administering a pharmaceutical composition comprising a compound having formula (I) with R1–R8 defined and pharmaceutically acceptable salt/isomer/tautomer/hydrate/solvate, where R2 is a linker-non-glycomimetic moiety with linker —C(=O)NH(CH2)1-4NHC(=O)— and the non-glycomimetic moiety comprises polyethylene glycol.
Treating cancer with elevated sialyl Lea and sialyl Lex ligands
A method for treating cancer in a subject with elevated expression of E-selectin binding ligands sialyl Lea and sialyl Lex as determined by antibodies directed against cancer-associated antigens CA-19-9 and/or CD65 by administering a pharmaceutical composition comprising a compound having formula (I) with R1–R8 defined and pharmaceutically acceptable salt/isomer/tautomer/hydrate/solvate, where R2 is a linker-non-glycomimetic moiety with linker —C(=O)NH(CH2)1-4NHC(=O)— and the non-glycomimetic moiety comprises polyethylene glycol.
Treating cancer with elevated sialyl Lea and sialyl Lex ligands
A method for treating cancer in a subject with elevated expression of E-selectin binding ligands sialyl Lea and/or sialyl Lex as determined by antibodies directed against HECA-452 and/or FH-6 by administering a pharmaceutical composition comprising a compound having formula (I) with R1–R8 defined and pharmaceutically acceptable salt/isomer/tautomer/hydrate/solvate, where R2 is a linker-non-glycomimetic moiety with linker —C(=O)NH(CH2)1-4NHC(=O)— and the non-glycomimetic moiety comprises polyethylene glycol.
Across the independent claims, coverage is directed to administering a formula (I) E-selectin antagonist compound or pharmaceutically acceptable derivative featuring a defined linker-non-glycomimetic moiety with a polyethylene glycol component, with patient selection framed by hematopoietic stem cell chemosensitivity/radiosensitivity reduction or cancer treatment guided by E-selectin activity or E-selectin binding ligand expression.
Stated Advantages
Reducing chemosensitivity or radiosensitivity of hematopoietic stem cells to at least one chemotherapeutic drug or radioactive therapy.
Treating cancer in a subject with highly active E-selectin as determined by the genetic polymorphism for E-selectin of S128R.
Treating cancer in subjects with elevated expression of E-selectin binding ligands sialyl Lea and/or sialyl Lex as determined by antibodies directed against specified cancer-associated antigens or markers.
Treating and/or preventing diseases by inhibiting E-selectin–ligand interactions.
Inhibiting tumor infiltration into bone marrow.
Reducing tumor cell adhesion to endothelial cells, including within bone marrow.
Reducing thrombosis and thrombus formation, including venous thromboembolism, deep vein thrombosis, and pulmonary embolism.
Documented Applications
Treating and/or preventing diseases associated with E-selectin ligand binding, including cancer progression and metastasis.
Reducing chemosensitivity or radiosensitivity of hematopoietic stem cells to at least one chemotherapeutic drug or radioactive therapy in a subject.
Treating cancer in subjects expressing highly active E-selectin determined by the genetic polymorphism for E-selectin of S128R.
Treating cancer in subjects with elevated E-selectin binding ligands sialyl Lea and sialyl Lex as determined by antibodies directed against cancer-associated antigens CA-19-9 and/or CD65.
Treating cancer in subjects with elevated E-selectin binding ligands sialyl Lea and/or sialyl Lex as determined by antibodies directed against HECA-452 and/or FH-6.
Use as therapy and/or adjunct in combination with chemotherapy and radiotherapy.
Use in relation to competing E-selectin binding agents such as antibodies, polypeptides, peptides, or aptamers that bind E-selectin.
Interested in licensing this patent?