Ship inhibitors and uses thereof
Inventors
Kerr, William G. • Chisholm, John D.
Assignees
Syracuse University • Research Foundation of the State University of New York
Publication Number
US-11319336-B2
Publication Date
2022-05-03
Expiration Date
2031-04-11
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Abstract
The present invention relates to SHIP inhibitor compounds and methods for using these compounds. In particular, the present invention discloses the following methods: (i) a method of treating graft versus host disease in a subject; (ii) a method of inhibiting a SHIP1 protein in a cell; (iii) a method of selectively inhibiting a SHIP1 protein in a cell; (iv) a method for treating or preventing graft-versus-host disease (GVHD) in a recipient of an organ or tissue transplant; (v) a method of modulating SHIP activity in a cell expressing SHIP1 or SHIP2; (vi) a method of ex vivo or in vitro treatment of transplants; (vii) a method of inhibiting tumor growth and metastasis in a subject; (viii) a method of treating a hematologic malignancy in a subject; (ix) a method of inducing apoptosis of multiple myeloma cells; (x) a method of treating multiple myeloma in a subject; (xi) a method of inhibiting the proliferation of a human breast cancer cell; and (xii) a method of treating breast cancer in a subject.
Core Innovation
The present invention provides small molecule SHIP inhibitor compounds of the specified formula (I), including their pharmaceutically acceptable salts, for use as therapeutic agents. These compounds, also referred to as SHIP1 inhibitors or SHIP inhibitor compounds, are in certain embodiments selective inhibitors of SHIP1. An extensive range of substituents is defined for the various positions (R1, R2, R3, R4, R5, R13, X1, and X2) of the compound, with particular embodiments described to exemplify possible structures.
The invention addresses the need for SHIP1 selective inhibitors capable of increasing granulocyte and myeloid immunoregulatory (MIR) cell production in vivo and promoting apoptosis of blood cell cancers. Background studies indicate that SHIP1-deficient hosts are permissive for mismatched bone marrow grafts, show reduced graft-versus-host disease (GVHD), and have increased MIR cell and granulocyte numbers, making SHIP1 a target for facilitating transplantation and reducing harmful immune responses.
The invention encompasses methods for treating or preventing GVHD in organ or tissue transplant recipients, inhibiting SHIP1 or SHIP2 protein in cells, modulating SHIP activity, ex vivo or in vitro treatment of transplants, inhibiting tumor growth and metastasis, treating hematologic malignancies, inducing apoptosis in multiple myeloma cells, treating multiple myeloma and breast cancer, treating myelosuppression and anemia, increasing platelets, aiding post-bone marrow transplant recovery, and enhancing blood stem cell harvest. The invention further provides compositions and regimens for clinical use of these inhibitors alone or in combination with other therapeutic agents.
Claims Coverage
The patent has several independent claims centered on pharmaceutical compositions and SHIP inhibitor compounds, detailing specific chemical structures and therapeutic uses.
Pharmaceutical compositions comprising SHIP inhibitor compounds of formula (I)
A pharmaceutical composition that includes a SHIP inhibitor compound of formula (I) or its pharmaceutically acceptable salt, where the formula (I) is explicitly defined by the positions and substituents R1, R2, R3, R4, R5, R13, X1, and X2 as described. - The compounds are characterized by specific chemical structures and substituents detailed in the patent. - The pharmaceutical composition can be used for administration to mammals, including humans.
Pharmaceutical compounds of defined formula
A pharmaceutical compound described by a specific formula as provided in the detailed claim text, where X, R, and other substituents are defined as in the patent. - These compounds may have variations where X is not present, or where the compound is a pharmaceutically acceptable salt.
In summary, the inventive features cover pharmaceutical compositions and individual compounds of defined steroid-based structures with specified substituents, as well as their salts and formulations. The claims emphasize the chemical definition and intended pharmaceutical use of these SHIP inhibitor compounds.
Stated Advantages
The SHIP1 inhibitor compounds significantly expand the myeloid immunoregulatory cell compartment and impair priming of allogeneic T cell responses, facilitating tolerance in transplantation.
Treatment with SHIP1 inhibitors increases granulocyte production without triggering the myeloid-associated lung consolidation seen in genetic SHIP1 deficiency models.
SHIP1 inhibitors promote apoptosis of blood cancer cells and reduce tumor growth and metastasis.
SHIP inhibitors offer a selective method to dampen harmful host and donor allogenic T cell responses without significantly compromising adaptive immune functions.
SHIP inhibitors can enhance engraftment of donor bone marrow and reduce the incidence and severity of GVHD while preserving normal humoral immunity.
Granulocyte recovery after myeloablative therapies is improved, supporting recovery after bone marrow transplants.
Some deleterious effects of genetic SHIP1 deficiency, particularly lung pathology, are notably absent with chemical inhibition, suggesting an improved safety profile.
Documented Applications
Treatment and prevention of graft-versus-host disease in recipients of organ or tissue transplants.
Inhibition and selective inhibition of SHIP1 protein in cells.
Modulation of SHIP activity in cells expressing SHIP1 or SHIP2 to prevent autoimmune disease, GVHD, and solid organ graft rejection.
Ex vivo or in vitro treatment of blood derived cells, bone marrow transplants, or organ transplants to inactivate T-lymphocytes.
Inhibition of tumor growth and metastasis in subjects.
Treatment of hematologic malignancies, including leukemia, lymphoma, multiple myeloma, myelodysplastic syndrome, and myeloproliferative diseases.
Induction of apoptosis in multiple myeloma cells.
Treatment of multiple myeloma in a subject.
Inhibition of proliferation of human breast cancer cells and treatment of breast cancer in a subject.
Treatment of myelosuppression in a subject.
Treatment of anemia in a subject.
Increasing platelet levels in a subject.
Aiding recovery after bone marrow transplant by increasing production of blood cell components.
Enhancing blood stem cell harvest by mobilizing stem cells from bone marrow to blood.
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