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 • Wang, Chen
Assignees
University of Kansas • Northwestern University • US Department of Health and Human Services
Publication Number
US-10301314-B2
Publication Date
2019-05-28
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 for reducing the prevalence of the perinucleolar compartment (PNC) in cells, particularly compounds of formula (I) with various substituents as defined in the patent. These compounds are useful in treating diseases or disorders associated with increased PNC prevalence, such as cancer, specifically metastatic cancer. The invention also discloses pharmaceutical compositions containing these compounds and methods for disrupting the PNC, reducing PNC prevalence, and treating or preventing cancer in mammals by administering these compounds.
The problem being addressed stems from the significant role of metastasis in the spread of cancer and its responsibility for the majority of cancer-related deaths. While the understanding of metastasis mechanisms has advanced, therapeutic tools specifically targeting metastasis remain very limited. The PNC is a subnuclear structure associated with malignancy and metastasis, with its prevalence correlating positively with metastatic capacity of tumors. Existing anticancer agents that reduce PNC prevalence do so by causing cytotoxic effects, making it challenging to separate antimetastatic activity from cell death. There is an unmet need for agents that can selectively disrupt or reduce the PNC without overt cytotoxicity to inhibit cancer metastasis effectively.
Claims Coverage
The patent includes one independent claim detailing a method for treating cancer in mammals by administering a specified class of compounds. The inventive features focus on the chemical nature of the compounds, the cancer types treated, combinations with other therapies, and specific therapeutic effects achieved.
Method for treating cancer with compounds of formula (I)
Administering to a mammal a compound of formula (I) defined by substituents R1, R2, R3, and R4 with detailed chemical structures and substitutions specifically designed to reduce PNC prevalence and treat cancer.
Use of specific substituents on the compound structure
Selection of R1 from a defined group of chemical moieties including heterocyclyl and hydroxyalkyl groups, R2 and R3 as phenyl groups, and R4 as benzyl or variants such as 4-methoxybenzyl, phenylethyl, or other specified substituents to optimize therapeutic activity.
Treatment of pancreatic cancer
Utilizing the compounds for the treatment of pancreatic cancer as an explicit cancer indication.
Combination with chemotherapeutic or radiation treatments
The method further comprises coadministering the compound with a chemotherapeutic agent or subjecting the mammal to radiation therapy to enhance anticancer efficacy.
Therapeutic outcomes including PNC disruption and reduction of cancer cell activities
Treatment results in disrupting the PNC in cells, reducing PNC prevalence, lowering ATP levels in metastatic cancer cells, decreasing colony formation, and inhibiting cancer cell migration in the mammal.
The independent claim defines a method of cancer treatment centered on administering precisely defined compounds of formula (I), specifying compound structure features, targeted cancer types (including pancreatic cancer), combination with other cancer therapies, and the biological outcomes achieved, such as PNC disruption and inhibition of metastasis-related cellular functions.
Stated Advantages
Selective inhibition of anchorage independent growth of metastatic cancer cells at very low concentrations without impacting cell viability.
Disruption and reduction of the perinucleolar compartment prevalence correlates with decreased metastatic potential.
Use of compounds that reduce PNC prevalence without overt cytotoxicity, addressing the need to separate antimetastatic effects from general cell death.
Potential enhancement or potentiation of anticancer therapies, including chemotherapeutic agents and radiation treatment, via coadministration.
Documented Applications
Treatment of a broad range of cancers, especially metastatic cancers such as breast, ovarian, colorectal, brain, prostate, and pancreatic cancers.
Use as therapeutic agents to disrupt or reduce the perinucleolar compartment in cancer cells.
Co-administration with anticancer agents including reversible DNA binders, DNA alkylators, DNA strand breakers, and radiation therapy.
Reduction of ATP levels produced by metastatic cancer cells, inhibition of cancer cell colony formation, and inhibition of cancer cell migration in vivo.
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