Schweinfurthins and uses thereof
Inventors
Reilly, Karlyne • Turbyville, Thomas • Beutler, John A. • Wiemer, David
Assignees
University of Iowa Research Foundation UIRF • US Department of Health and Human Services
Publication Number
US-8686016-B2
Publication Date
2014-04-01
Expiration Date
2030-04-30
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Abstract
Disclosed is a method for preventing or treating an undesirable condition in a subject carrying cells homozygous null for the neurofibromatosis type 1 gene or subjects that are haploinsufficient for the neurofibromatosis type 1 gene, the method comprising administering to a subject in need thereof an effective amount of a schweinfurthin or schweinfurthin analog or derivative, or a pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof. Also disclosed is a new schweinfurthin compound of the formula.
Core Innovation
The invention provides methods for preventing or treating undesirable conditions in subjects carrying cells homozygous null for the neurofibromatosis type 1 gene (NF1−/−) or subjects haploinsufficient for the gene (NF1−/+). The method comprises administering to such subjects an effective amount of a schweinfurthin, schweinfurthin analog or derivative, or pharmaceutically acceptable salts, prodrugs, hydrates, or solvates thereof.
The invention also provides compounds of specific formulas as schweinfurthins or their analogs and pharmaceutical compositions containing these compounds and acceptable carriers, for the prevention or treatment of NF1-associated conditions. It discloses new schweinfurthin compounds with structural modifications and combinations.
The problem addressed is the lack of treatments for neurofibromatosis type 1, a common genetic disease with complex benign and malignant manifestations including tumors and various systemic abnormalities. NF1 patients face increased mortality and reduced quality of life, and current therapies are inadequate. There is an unmet need for NF1-specific drugs, especially targeting cells deficient or haploinsufficient in NF1 gene function, to treat tumors and other manifestations associated with this condition.
Claims Coverage
The claims cover eight main inventive features encompassing methods, compounds, pharmaceutical compositions, and combination therapies related to schweinfurthins for treating NF1-related conditions.
Method for preventing or treating NF1-related conditions using schweinfurthins excluding schweinfurthin A
A method of preventing or treating an undesirable condition in a subject carrying NF1 homozygous null or haploinsufficient cells by administering a schweinfurthin or analog, excluding schweinfurthin A, including pharmaceutically acceptable salts, prodrugs, hydrates, or solvates.
Use of specific schweinfurthin analogs for treatment
Use of schweinfurthin B, 3-deoxyschweinfurthin B, 5'-methylschweinfurthin E, or 5'-methylschweinfurthin G as the active compound in the method.
Combination therapy methods
Methods comprising separate, simultaneous, or sequential administration of schweinfurthin compounds with at least one additional compound that modulates neurofibromatosis type 1 pathways.
Compounds of defined chemical formulas
Specific schweinfurthin compounds characterized by chemical formulae I and others, including pharmaceutically acceptable salts, prodrugs, hydrates, or solvates thereof.
Pharmaceutical compositions including schweinfurthins and ras pathway inhibitors
Pharmaceutical compositions comprising schweinfurthin compounds and pharmaceutically acceptable carriers, optionally combined with at least one ras pathway inhibitor.
Methods for treating non-tumor NF1 manifestations
Methods using schweinfurthins or analogs, including schweinfurthin A and others, to prevent or treat non-tumor manifestations of neurofibromatosis type 1 such as pseudarthrosis, vasculopathy, or learning disabilities.
Use of schweinfurthins to treat peripheral nervous system conditions
Methods for treating undesirable peripheral nervous system conditions including malignant peripheral nerve sheath tumors with schweinfurthins or analogs.
Therapeutic method targeting neurofibromatosis type 1
A method wherein the undesirable condition treated is neurofibromatosis type 1 itself, using schweinfurthin compounds.
The claims comprehensively cover methods of treatment using various schweinfurthin compounds and analogs, pharmaceutical compositions including those compounds and combination therapies, and cover both tumor and non-tumor clinical manifestations related to NF1 gene deficiencies.
Stated Advantages
Schweinfurthins provide selective cytotoxicity toward NF1-null and NF1-haploinsufficient tumor cells while sparing non-tumor cells such as primary astrocytes, offering a potential therapeutic window.
They represent a new pharmacophore with a novel mode of action, potentially leading to new classes of NF1-specific therapies.
Certain synthetic schweinfurthin analogs show improved chemical stability and maintained potency.
Schweinfurthins can be formulated for various administration routes and combined with other therapeutic agents for enhanced NF1 pathway modulation.
Documented Applications
Treatment and prevention of tumors associated with NF1 gene loss, including gliomas, malignant peripheral nerve sheath tumors (MPNSTs), astrocytomas, glioblastomas, pheochromocytomas, rhabdomyosarcomas, and juvenile myelomonocytic leukemia.
Treatment and prevention of non-tumor manifestations of NF1, such as pseudarthrosis, vasculopathy, and learning disabilities.
Use in subjects carrying NF1 homozygous null or haploinsufficient cells to prevent or treat undesirable conditions related to neurofibromatosis type 1.
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