2004 – Edward C. Taylor
The Discovery of Alimta™, A Broadly Effective New Antitumor Agent
The pteridine ring system was first identified in a study of the constituents of butterfly wing pigments, and pteridines thus were initially viewed as occupying an esoteric, insignificant corner of natural product chemistry We now know, however, that two pteridine derivatives, the molybdenum cofactor and folic acid, are critical components of all living cells, and are required for all forms of life. Cofactors derived from folic acid play key roles in a host of diverse metabolic reactions essential for the formation of DNA, RNA, ATP, amino acids and proteins. Our long-time fascination with pteridine chemistry has developed into a search for inhibitors of folate-dependent enzymes, and led a few years ago to the discovery that (6R)-5,10-dideaza-5,6.7,8-tetrahydrofolic acid (lometrexol) blocked de novo purine biosynthesis, and exhibited excellent therapeutic activity against a variety of solid tumors. These initial observations initiated an intensive search for further inhibitors of folate-dependent processes. This effort has culminated in the discovery of a remarkable new oncolytic agent, Alimta™ (pemetrexed disodium, now under development by Eli Lilly & Company). Alimta™ exhibits an unprecedented breadth of antitumor activity that results from inhibition of at least five of the major folate-dependent enzymes in cellular metabolism. Every type of solid tumor thus far examined clinically has responded to this new agent. Alimta™ is now in multiple advanced Phase II/III trials and has recently been approved for compassionate use in mesothelioma. This lecture will attempt to describe the tortuous explorations that eventually led to the discovery of Alimta™, its current clinical status, and our understanding of its unique mode of action.