Compounds and methods for the prevention and treatment of tumor metastasis and tumorigenesis
Inventors
Frankowski, Kevin • Patnaik, Samarjit • Huang, Sui • Marugan, Juan Jose • Norton, John • Schoenen, Frank J. • Southall, Noel Terrence • Titus, Steven • Zheng, Wei
Assignees
University of Kansas • Northwestern University • US Department of Health and Human Services
Publication Number
US-9663521-B2
Publication Date
2017-05-30
Expiration Date
2032-12-17
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Abstract
The disclosure provides compounds for reducing the prevalence of the perinucleolar compartment in cells, for example, of formula (I), wherein R1, R2, R3, and R4 are as defined herein, that are useful in treating a disease or disorder associated with increased prevalence of the perinucleolar compartment, such as cancer. Also disclosed is a composition containing a pharmaceutically acceptable carrier and at least one compound embodying the principles of the invention, and a method of treating or preventing cancer in a mammal.
Core Innovation
The invention provides compounds of formula (I) that reduce the prevalence of the perinucleolar compartment (PNC) in cells. These compounds are useful in treating diseases or disorders associated with increased prevalence of the PNC, such as cancer. The compounds disrupt the assembly of the PNC, a subnuclear body located at the periphery of the nucleolus and associated with malignancy both in vitro and in vivo, particularly metastatic cancers.
The PNC is highly prevalent in metastatic tumor cells and its presence positively correlates with metastatic capacity, making it a marker for cancer development and prognosis. Current therapeutic tools specifically targeting the metastatic process are limited, and PNC reduction represents a phenotypic change indicative of inhibition of cellular malignancy. The invention includes methods for using these compounds as therapeutic agents for treating or preventing cancer, pharmaceutical compositions containing these compounds, and methods for disrupting the PNC in cells.
Claims Coverage
The patent contains two independent claims that cover compounds of formula (I) and pharmaceutical compositions thereof.
Compounds of formula (I)
Compounds defined by formula (I) with variable substituents R1, R2, R3, and R4, where each substituent is selected from specified groups including alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and various substituted derivatives, with provisos restricting specific combinations to ensure novelty and activity.
Pharmaceutical composition comprising the compounds
Compositions containing a pharmaceutically acceptable carrier and at least one compound or pharmaceutically acceptable salt of the compound of formula (I) as active ingredients.
The claims cover the novel chemical compounds characterized by diverse substituents and their use in pharmaceutical compositions for treating diseases associated with PNC prevalence, specifically cancer, highlighting the structural diversity and medicinal applicability of the compounds.
Stated Advantages
The compounds reduce the prevalence of the perinucleolar compartment, which correlates with metastatic capacity in cancer cells, thereby targeting metastatic cancer specifically.
They disrupt the PNC assembly without overt cytotoxicity, distinguishing their anti-metastatic effect from general cytotoxic effects.
The compounds inhibit anchorage independent growth and migration of cancer cells, demonstrating potent inhibition of malignant properties.
Documented Applications
Treatment or prevention of cancer, particularly metastatic cancers with high PNC prevalence.
Use in combination with anticancer agents such as reversible DNA binders, DNA alkylators, and DNA strand breakers to potentiate or enhance anticancer activity.
Potentiating or enhancing anticancer activity of radiation treatment by coadministration with radiation therapies.
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