Selective ship inhibitors for treating disease
Inventors
Kerr, William G. • Chisholm, John D.
Assignees
Syracuse University • Research Foundation of the State University of New York
Publication Number
US-11952328-B2
Publication Date
2024-04-09
Expiration Date
2039-10-17
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Abstract
The present disclosure provides compositions that inhibit the SH2-containing inositol 5′phosphatase (SHIP) as well as methods using such composition for use in treating or ameliorating the effects of a medical condition in a subject. For examples, compositions including the general formulaas disclosed herein are suitable for use herein.
Core Innovation
The invention provides compositions that inhibit the SH2-containing inositol 5′-phosphatase 1 (SHIP1) and methods for using such compositions to treat or ameliorate medical conditions in subjects. The invention specifically discloses compounds, including 8-((2-aminoethyl)amino)naphthalene-1-sulfonic acid and related structures, that act as selective SHIP1 inhibitors. These compounds are suitable for pharmaceutical use and can be formulated as pharmaceutically acceptable salts or solvates.
The problem addressed by the invention is the need for compounds that increase natural killer (NK) cell and T cell responsiveness and prevent hyporesponsiveness caused by prolonged or unopposed SHIP1 activation, which is implicated in diseases where immune cell responses are critical, such as cancer. Existing treatments for related side effects of chemotherapy and immune regulation, such as growth factors for blood cell production, often require injection and have limited efficacy, indicating an unmet need for novel, more effective oral therapeutics.
The core innovation lies in the use of selective SHIP1 inhibitors to enhance host defense mechanisms by promoting the activation and responsiveness of NK cells and T cells. The compounds not only inhibit SHIP1 activity but also directly or indirectly facilitate cytotoxic lymphocyte-mediated clearance of tumor cells and ameliorate conditions such as anemia by increasing hematopoiesis. The document provides detailed chemical structures and dosing regimens for these novel SHIP1 inhibitors and their application in various diseases.
Claims Coverage
There is one independent claim in this patent, which defines the main inventive feature.
Method for inhibiting SHIP1 using 8-((2-aminoethyl)amino)naphthalene-1-sulfonic acid
A method for inhibiting SH2-containing inositol 5′-phosphatase 1 (SHIP1) in a subject comprises administering an effective amount of 8-((2-aminoethyl)amino)naphthalene-1-sulfonic acid, or a pharmaceutically acceptable salt thereof. This feature covers the use of the specified compound as a SHIP1 inhibitor, emphasizing: - Administration to a subject - The amount is effective for inhibition of SHIP1 - The active moiety is 8-((2-aminoethyl)amino)naphthalene-1-sulfonic acid or its pharmaceutically acceptable salt.
The claim coverage is centered on the use of 8-((2-aminoethyl)amino)naphthalene-1-sulfonic acid for SHIP1 inhibition in subjects, providing specificity for the compound and its application as a method for enzyme inhibition.
Stated Advantages
Selective SHIP1 inhibition increases NK and T cell responsiveness and prevents hyporesponsiveness caused by chronic SHIP1 activation.
Compounds can directly induce apoptosis of malignant cells and activate NK and T cell-mediated immune responses, resulting in improved tumor clearance and increased survival in tumor-bearing hosts.
Pharmaceutical compositions can be formulated for oral or parenteral administration, providing dosing flexibility and potential ease of administration.
The method provides a novel chemo-immunotherapeutic that can simultaneously promote immune efficacy and direct cell killing.
Documented Applications
Treatment of hematopoietic malignancies, including leukemia, acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), Hodgkin's lymphoma, non-Hodgkin's lymphoma, and multiple myeloma.
Activation of NK cells and T cells to increase host defense against malignancy in a subject.
Treatment of anemia, thrombocytopenia, or neutropenia arising from chemotherapy, radiation, bone marrow disease, infections, or congenital disorders.
Treatment of graft-versus-host disease (GvHD) after organ or bone marrow transplantation.
Treatment of non-hematologic (e.g., epithelial) malignancies by promoting anti-tumor NK and/or T cell responses.
Increase in hematopoiesis in a subject in need thereof.
Activating natural killer (NK) cells ex vivo.
Treating illnesses or conditions for which NK cells and/or T cells provide a host defense, including viral infection, bacterial infection, or cancer.
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