Method of inhibiting ABCG2 and other treatment methods
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-9314448-B2
Publication Date
2016-04-19
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): 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 mammals by administering an effective amount of a chemotherapeutic agent in conjunction with an effective amount of compounds that inhibit the ABCG2 protein. These compounds are defined by a general formula (I), with specific substituents and configurations described within the patent. The inhibition of ABCG2 leads to enhanced chemotherapeutic treatment and reduced resistance of cancer cells to chemotherapeutic agents.
The problem addressed by the invention is multidrug resistance in cancer chemotherapy, primarily mediated by the multidrug resistance transporter ABCG2. ABCG2 is known to limit the oral absorption of some drugs and is involved in resistance to various anti-cancer drugs, including mitoxantrone, topotecan, irinotecan, flavopiridol, and methotrexate. There is a lack of clinically useful ABCG2 inhibitors, which impedes effective chemotherapy. The invention aims to provide compounds that inhibit ABCG2, thereby overcoming resistance and increasing the efficacy of chemotherapy.
In addition to inhibiting ABCG2, the invention covers methods of inhibiting related transporters Pgp and MRP1 to reduce multidrug resistance. The methods also include increasing the bioavailability of ABCG2 substrate drugs by co-administering these compounds. The patent also discloses novel compounds of formula (II) and pharmaceutical compositions containing these compounds for the described uses.
Claims Coverage
The patent contains two independent claims directed to methods of inhibiting ABCG2 in mammals afflicted with cancer, each claim involving administration of a compound of formula (I) to inhibit ABCG2 protein.
Method of inhibiting ABCG2 using compounds of formula (I)
Administering to a mammal afflicted with cancer an effective amount of a compound of formula (I) to inhibit the ABCG2 protein, wherein the compound includes specific substituents R1, R2, R3, X1, and X2 as described, with the proviso that the compound is not botryllamide C.
Selection of compound substituents to enhance efficacy
Choosing substituents where R1 and R2 are hydrogen or C1-C6 alkyl; X1 and X2 independently selected from hydrogen and halo; R3 is hydrogen; and selecting compounds from the group consisting of botryllamide A, B, D, E, F, G, I, J and combinations thereof, particularly botryllamide I or J.
Reduction of chemotherapeutic resistance by inhibiting ABCG2
Administering the compound of formula (I) to a mammal to reduce the resistance of the mammal’s cancer to a chemotherapeutic agent by inhibiting ABCG2 protein.
The independent claims cover methods of inhibiting ABCG2 to reduce cancer resistance and improve chemotherapeutic efficacy by administering specific compounds of formula (I) with defined substituents, highlighting particular botryllamides, and excluding botryllamide C.
Stated Advantages
Inhibitors of ABCG2 can enhance the efficacy of chemotherapy by overcoming multidrug resistance.
ABCG2 inhibitors can increase the bioavailability and brain penetration of ABCG2 substrate drugs.
The compounds also inhibit related multidrug resistance transporters Pgp and MRP1, broadening their therapeutic utility.
Documented Applications
Enhancing chemotherapeutic treatment of tumor cells in mammals by co-administration of ABCG2 inhibitor compounds with chemotherapeutic agents.
Reducing resistance of cancer cells to chemotherapeutic agents by inhibiting ABCG2, Pgp, and/or MRP1 transporters in mammals.
Increasing the bioavailability and brain penetration of ABCG2 substrate drugs, useful in treating brain tumors, CNS metastases, and gastrointestinal stromal tumors.
Treatment of various cancers including leukemias (e.g., AML, CML), solid tumors (lung, endometrium, digestive tract), melanomas, non-small cell lung cancer, colon, prostate, brain, lymphoma, breast, ovarian, lung, and stomach tumors.
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