Therapeutic compounds and methods
Inventors
Rishi, Arun K. • Larsen, Scott D.
Assignees
Wayne State University • US Department of Veterans Affairs • University of Michigan Ann Arbor
Publication Number
US-9598441-B2
Publication Date
2017-03-21
Expiration Date
2032-08-30
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Abstract
The invention provides compounds of formula I: and salts thereof. The invention also provides pharmaceutical compositions comprising a compound of formula I, processes for preparing compounds of formula I, intermediates useful for preparing compounds of formula I and therapeutic methods for treating cancer using compounds of formula I.
Core Innovation
The invention provides compounds of formula I and their pharmaceutically acceptable salts as therapeutic agents for treating cancer, including breast cancer, pancreatic cancer, and mesotheliomas. It also encompasses pharmaceutical compositions comprising these compounds, methods for preparing both the compounds and useful intermediates, and therapeutic methods utilizing the compounds for cancer treatment.
The background identifies a problem in cancer therapy related to the frequent alteration of cell division cycle and apoptosis pathways, especially in inflammation-associated disorders such as cancers. The document notes the importance of regulators of mitotic control and apoptosis signaling as targets for intervention. Specifically, the protein CARP-1/CCAR1 regulates chemotherapy-dependent apoptosis signaling, and its interactions with components of the anaphase promoting complex/cyclosome (APC/C), particularly APC-2, influence cell growth and apoptosis.
The invention addresses the need for novel agents that treat various cancers, including drug resistant breast cancers, by providing new compounds that inhibit the growth of these cancers via mechanisms involving modulation of CARP-1 interactions with APC/C components. The compounds antagonize CARP-1 binding with APC-2, ultimately leading to cell cycle arrest and induction of apoptosis.
Claims Coverage
The patent includes multiple independent claims directed to compounds of formula I, pharmaceutical compositions comprising these compounds, and methods of treating cancer using these compounds. The claims cover the structural features of the compounds and their therapeutic applications.
Compounds of formula I with specific substitution patterns
The invention provides compounds of formula I characterized by specific R group substitutions defining aryl, alkylaryl, heteroaryl, alkylheteroaryl moieties, and pharmaceutically acceptable salts thereof. Specific embodiments include compounds wherein R2a and R2b are oxo, and where substitutions allow for diverse functional groups such as halogens, alkyl, alkenyl, alkynyl, carbocycles, and amino derivatives.
Pharmaceutical compositions comprising compounds of formula I
Compositions containing a compound of formula I or its pharmaceutically acceptable salt combined with a pharmaceutically acceptable carrier are claimed for therapeutic use.
Methods for treating cancer using compounds of formula I
Methods for treating cancers including breast cancer (including drug resistant variants), pancreatic cancer, and mesotheliomas by administering an effective amount of a compound of formula I or its pharmaceutically acceptable salts to a mammal are disclosed.
Methods of treating cancer using a particular subclass of compounds of formula I (formula Ia)
Claims extend to methods for treating cancer using compounds of formula Ia (a specific subset of formula I compounds) with defined substitution patterns on R3 and R1, supporting diverse chemical groups and substitution patterns.
The independent claims comprehensively cover the novel chemical entities represented by formula I, their pharmaceutical compositions, and methods for cancer treatment where these compounds achieve therapeutic effects by modulating cancer cell growth and apoptosis through interference with CARP-1 binding to APC-2.
Stated Advantages
Compounds selectively inhibit growth of various cancer cells including drug resistant breast cancer cells, while sparing non-tumorigenic immortalized mammary epithelial cells, suggesting a suitable safety profile.
The compounds induce G2M cell cycle arrest, stimulate apoptosis involving activation of caspases, and lead to depletion of cyclin B1 and Cdc20 proteins, which are key regulators of mitosis.
The compounds function by binding to CARP-1 and antagonizing its interaction with APC-2, thereby modulating APC/C activity and promoting tumor suppressive pathways.
Documented Applications
Treatment of breast cancer, including drug resistant forms such as tamoxifen- and adriamycin-resistant breast cancers, triple negative breast cancers, and HER-2-positive breast cancers.
Treatment of pancreatic cancer.
Treatment of mesotheliomas, including malignant pleural mesothelioma and mesothelial lung cancer.
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