Botryllamides and method of inhibiting PGP in a mammal afflicted with cancer
Inventors
Henrich, Curtis J. • Bokesch, Heidi R. • Cartner, Laura K. • Fuller, Richard W. • Gustafson, Kirk R. • Takada, Kentaro • McMahon, James B. • Bates, Susan E. • Robey, Robert W. • Shukla, Suneet • Ambudkar, Suresh V. • Dean, Michael C.
Assignees
US Department of Health and Human Services
Publication Number
US-8470888-B2
Publication Date
2013-06-25
Expiration Date
2028-12-29
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Abstract
Disclosed are methods of enhancing the chemotherapeutic treatment of tumor cells, reducing resistance of a cancer cell to a chemotherapeutic agent, a method of inhibiting ABCG2, Pgp, or MRP1 in a mammal afflicted with cancer, and a method of increasing the bioavailability of an ABCG2 substrate drug in a mammal. The methods comprise administering effective amounts of certain compounds to the mammal, for example, a compound of the formula (I): Formula (I), wherein R1, R2, R3, X1, X2, X3, a, and b are as described herein. Uses of these compounds in the preparation of a medicament are also disclosed. Also disclosed are compounds of formula (II), pharmaceutical compositions comprising such compounds and uses thereof.
Core Innovation
The invention provides methods of enhancing the chemotherapeutic treatment of tumor cells in a mammal by administering effective amounts of chemotherapeutic agents in conjunction with compounds that inhibit the ABCG2 protein. These compounds belong to specified chemical formulas, excluding botryllamide C, and serve to inhibit ABCG2, Pgp, and/or MRP1, thereby increasing the efficacy of chemotherapeutic agents and reducing cancer cell resistance.
The problem being solved is multidrug resistance in cancer chemotherapy due to the multidrug resistance transporter ABCG2, a member of the ABC family of membrane transport proteins that limits drug absorption and causes resistance to various anti-cancer drugs. Few clinically useful inhibitors of ABCG2 have been reported, and this invention addresses the need for compounds that inhibit ABCG2 to improve chemotherapy effectiveness.
The invention further provides compounds of formula (II), pharmaceutical compositions comprising such compounds, and methods of using these compounds to inhibit ABCG2, Pgp, and MRP1 in mammals afflicted with cancer, as well as to increase the bioavailability of ABCG2 substrate drugs. These methods include administering effective amounts of these compounds with chemotherapeutic agents to reduce cancer drug resistance, enhance chemotherapeutic treatment, and increase bioavailability, with applicability across various cancers.
Claims Coverage
The claims include three inventive features focusing on isolated compounds, pharmaceutical compositions comprising these compounds, and methods of inhibiting Pgp in mammals afflicted with cancer.
Isolated compound of botryllamide I and botryllamide J
An isolated or purified compound selected from the group consisting of botryllamide I and botryllamide J.
Pharmaceutical composition comprising botryllamide I or botryllamide J
A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound selected from the group consisting of botryllamide I and botryllamide J.
Method of inhibiting Pgp in a mammal afflicted with cancer
Administering to the mammal a pharmaceutical composition comprising botryllamide I or botryllamide J to inhibit Pgp in a mammal afflicted with cancer.
The claims cover isolated botryllamide compounds, their pharmaceutical compositions, and their method of administration for inhibiting Pgp in cancer-afflicted mammals, focusing on compounds botryllamide I and J and their role in cancer treatment through Pgp inhibition.
Stated Advantages
The compounds inhibit ABCG2, Pgp, and MRP1, thereby enhancing the chemotherapeutic treatment efficacy of tumor cells and reducing cancer cell resistance to chemotherapeutic agents.
The methods can increase the bioavailability and brain penetration of ABCG2 substrate drugs, improving therapeutic outcomes especially for CNS tumors and metastases.
Compounds described offer potential oncologic and pharmacologic applications by overcoming multidrug resistance mechanisms in cancer cells.
Documented Applications
Enhancing chemotherapeutic treatment efficacy in mammals with cancer by coadministering ABCG2, Pgp, or MRP1 inhibitors with chemotherapeutic agents.
Reducing drug resistance to chemotherapeutic agents in cancer patients expressing ABCG2, Pgp, or MRP1 transporters.
Increasing the bioavailability and CNS penetration of ABCG2 substrate drugs, useful in treating brain tumors, CNS metastases, and gastrointestinal stromal tumors.
Treatment of various cancers including leukemias, solid tumors of lung, endometrium, digestive tract, melanomas, non-small cell lung cancers, colon, prostate, brain, lymphomas, breast, ovarian, lung, and stomach tumors using the compounds and methods disclosed.
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