New and Improved Chemotherapy Adjuvants: Folate Based Inactivators of O6-alkylguanine-DNA alkyltransferase (alkyltransferase)
Description of Invention: O6-Benzylguanine derivatives, some O6-benzylpyrimidines, and related compounds are known to be inactivators of the human DNA repair protein O6-alkylguanine-DNA alkyltransferase (alkyltransferase). This repair protein is the primary source of resistance many tumor cells develop when exposed to chemotherapeutic agents that modify the O6-position of DNA guanine residues. Therefore, inactivation of this protein can bring about a significant improvement in the therapeutic effectiveness of these chemotherapy drugs. The prototype inactivator O6-benzylguanine is currently in clinical trials in the United States as an adjuvant in combination with the chloroethylating agent 1, 3-bis (2-chloroethyl)-1-nitrosourea (BCNU) and the methylating agent temozolomide. A similar alkyltransferase inactivator, O6-(4-bromothenyl) guanine is in clinical trials in the UK.
This technology is directed to the discovery of a new class of potent alkyltransferase inactivators, based on folate ester derivatives of O6-benzyl-2’-deoxyguanosine and of O6-[4-(hydroxymethyl)benzyl] guanine. All the folate ester derivatives of O6-benzyl-2’-deoxyguanosine were able to sensitize human tumor cells to killing by 1, 3-bis (2-chloroethyl)-1-nitrosourea with O6-benzyl-3’-O-[gamma-folyl]-2’-deoxyguanosine being the most active. The 3’ ester was found to be more potent than the 5’ ester and was more than an order of magnitude more active than O6-benzylguanine, which is currently in clinical trials.
Applications:
Promising candidates as chemotherapy adjuvants for the treatment of cancer.
Therapeutic application for drug resistant tumors where acquired resistance is caused by O6-alkylguanine-DNA alkyltransferase.
Advantages:
The folate ester derivatives are highly water soluble.
Conjugation of folic acid to an alkyltransferase inactivating compound should allow targeting of delivery to cells that express folate receptor as many tumor cells are known to do.
Development Status:
The technology is currently in the pre-clinical stage of development.
Inventors:
Drs. Gary Pauly (NCI) Robert C. Moschel (NCI) Sahar Javanmard (NCI) et al.
Patent Status:
DHHS Reference No. E-200-2007/0 --
This technology consists of U.S. Provisional Application No. 60/915,510 foreign equivalents, entitled “Inactivators of O6-Alkylguanine-DNA Alkyltransferase”
Related Technologies: DHHS Reference No. E-274-2003/0, entitled "2-Amino-O4-Substituted Pteridines and Their Use as Inactivators of O6-Alkylguanine-DNA Alkyltransferase"
Licensing Status: Available for exclusive and non-exclusive licensing.
Portfolios: Cancer
Cancer -Therapeutics-Conventional Chemotherapy-Other Cancer -Therapeutics
For Additional Information Please Contact: Adaku Nwachukwu J.D.
NIH Office of Technology Transfer
6011 Executive Blvd, Suite 325
Rockville, MD 20852-3804
Phone: 301 435-5560
Email: madua@mail.nih.gov
Fax: 301 402-0220
