2-Aza-2-Desamino Analogues of 5,8 Dideazafolic Acid

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Intellectual Property

ID:		213
IP Type:		Licensable Technology
Title:		2-Aza-2-Desamino Analogues of 5,8 Dideazafolic Acid - PT594 Folic Acid Analogue
Inventor:		Rosowsky, A
Summary:		Methotrexate, an antifolate drug, has been used for many years in the treatment of cancer, but its use has often been by limited resistance of tumor cells to its effects. The potential therapeutic significance of folic acid analogues targeted against thymidylate synthase (TS) as opposed to DHFR led to the synthesis of quinazoline analogues. However, their clinical usefulness was hampered by hepatic and renal toxicities. The toxicity problem spurred the development of a second-generation family of folate-based TS inhibitors, which were weaker binders of purified TS in vitro, but also resulted in an increased inhibitory potency against intact cells in culture. A researcher has synthesized folate analogues in which C2 and the associated H or methyl substituent of the standard desamino-5,8-dideazafolic acid compound have been replaced by nitrogen and a lone electron pair. These changes were made on the theory that (i) removal of H or Me might enable the molecule to extend more deeply into the active site pocket of the enzyme, and (ii) N2 might interact with active site residues by H-bonding, either directly or via a molecule of ordered water. Both of these properties were expected to be favorable for TS binding. Applications/Advantages: The compounds of the invention are potent inhibitors of DNA synthesis in mammalian cells. By inhibiting the conversion by the enzyme TS of dUMP into dTMP, a precursor necessary for DNA synthesis in treated cells is retarded. Thus, the compound is useful for the treatment of cancer or psoriasis, conditions characterized by overproliferation of cells.
Tech Type:		Therapeutics - Drugs
URL:		http://www.dfci.harvard.edu/res/technology/available.asp?case_number=213&keywords=&category_id=1&category_name=Therapeutics
Contact:		Ojas Mehta, Phone (617) 632-5807, Fax (617) 632-4012, Email Ojas_Mehta@dfci.harvard.edu
Organization:		Dana-Farber Cancer Institute

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