Inactivators of O6-alkylguanine-DNA alkyltransferase

Inventors

Moschel, Robert C. • MOSCHEL, LEGAL REPRESENTATIVE MATTHEW KARL, null • Pegg, Anthony E. • Javanmard, Sahar • Loktionova, Natalia • Pauly, Gary

Assignees

Penn State Research Foundation • US Department of Health and Human Services

Abstract

Disclosed are compounds that are AGT inactivators that include a folate residue, e.g., a compound of formula (I), wherein X1, X2, R1, and R2 are as described herein. Also disclosed is a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier. Also disclosed are methods of enhancing the chemotherapeutic treatment of tumor cells and inactivating AGT in a tumor cell. The methods comprise, inter alia, administering a compound or pharmaceutically acceptable salt of formula (I).

Core Innovation

The invention provides compounds that are O6-alkylguanine-DNA alkyltransferase (AGT) inactivators which include a folate residue, exemplified by compounds of formula (I) with defined substituents X1, X2, R1, and R2. These compounds exhibit high water solubility and include γ folate esters of O6-benzyl-2′-deoxyguanosine linked through the 3′ or 5′ hydroxyl, as well as folic acid γ esters of O6-[4-(hydroxymethyl)benzyl]guanine. The compounds and their pharmaceutically acceptable salts can be formulated into pharmaceutical compositions with carriers. Methods disclosed include enhancing chemotherapeutic treatment of tumor cells and inactivating AGT in tumor cells by administering an effective amount of these compounds with or without an antineoplastic alkylating agent.

AGT is a DNA repair protein that removes alkyl groups from the O6 position of guanine in DNA, thus protecting normal cells by preventing mutations that can initiate tumor formation. However, AGT also protects cancer cells by repairing DNA lesions caused by alkylating chemotherapeutic agents, reducing their efficacy. Existing approaches to modulate AGT include indirect depletion using methylating agents or direct inactivation using adjuvants such as O6-benzylguanine. While effective, direct inactivators have shown toxic side effects in clinical trials, indicating a need for improved compounds that are selective to tumor cells with reduced patient toxicity.

The invention addresses this need by providing folate-containing AGT inactivators that are highly water soluble and demonstrate increased selectivity for tumor cells. The folate residues facilitate selective uptake by tumors, enhancing tumor-specific alkyltransferase inactivation while reducing systemic toxicity. The compounds can be used therapeutically in chemotherapy by co-administration with antineoplastic alkylating agents that cause cytotoxic lesions at the O6 position of guanine, thereby potentiating their cytotoxicity. The invention includes pharmaceutical compositions suitable for various administration routes and describes methods of treatment enhancing chemotherapeutic effects through AGT inactivation in tumor cells.

Claims Coverage

The patent contains three independent claims focusing respectively on the compound formula (I), its pharmaceutical composition, and methods of treatment involving AGT inactivation and chemotherapy enhancement.

The independent claims cover novel folate-containing AGT inactivator compounds, their pharmaceutical formulations, and therapeutic methods that enhance the efficacy of alkylating chemotherapeutic agents by selectively inactivating AGT in tumor cells.

Stated Advantages

Documented Applications