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, 2-amino-O⁴-benzylpteridine derivatives targeted for use in cancer treatment in combination with chemotherapeutic agents such as 1, 3-bis (2-chloroethyl)-1-nitrosurea (BCNU) or temozolomide.  The derivatives of the present invention inactivate the O⁶-alkylguanine-DNA-alkyltransferase repair protein and thus enhance activity of such chemotherapeutic agents.  Some of the derivatives are water soluble and possess tumor cell selectivity in particular by inactivating alkyltransferase in tumor cells that overexpress folic acid receptors.  The 2-amino-O⁴-benzylpteridine derivatives represent a promising new class of alkyltransferase inactivator with representatives that may be great candidates as chemotherapy adjuvants.

Applications and Modality: 

• New small molecules as alkyltransferase inactivators based on 2-amino-O⁴-benzylpteridine compounds
• 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.

Publication:

ME Nelson, NA Loktionova, AE Pegg, RC Moschel. 2-amino- O⁴-benzylpteridine derivatives: potent inactivators of O⁶-alkylguanine-DNA alkyltransferase. J Med Chem. 2004 Jul 15;47(15):3887-3891.  [PubMed abs]

• U.S. Patent Application No. 10/585,566 filed 29 Aug 2006, claiming priority to 06 Jan 2004 (HHS Reference No. E-274-2003/0-US-03)
• Foreign equivalents

Inventors:

Robert C. Moschel (NCI) et al.

Licensees Sought:

Available for exclusive or non-exclusive licensing.