Developing a new class of anti-tumor agents: Molecular chaperones
Daniel T. Gewirth, Ph.D.

gewirthLife depends on the biochemical activity of the thousands of proteins that inhabit and decorate the surface of every one of our cells.

Proteins themselves, although simple linear combinations of the twenty amino acids, derive their remarkable properties from the complex three-dimensional structures into which they fold. Although in principle the precise three-dimensional structure for each protein is encoded in its linear chain of amino acids, in practice it is often impossible for a protein to achieve this final fold on its own in the context of the crowded cellular environment. As a result, cells have evolved a corps of proteins known as molecular chaperones that assist newly synthesized proteins as they adopt their active fold.

One such family of chaperones is known as the hsp90 family.  The list of “client” proteins of the hsp90 family reads like a Who’s Who of important therapeutic targets. The few known inhibitors of hsp90 chaperones exhibit potent anti-tumor activity, showing that preventing the proper folding of client proteins, many of which are implicated in cancer, can have profound therapeutic implications.

The Gewirth lab is studying this important family of chaperones. Using X-ray crystallography and biochemical analyses, we ask both fundamental questions about hsp90 function and mechanism, as well as practical questions related to the development of novel compounds that can specifically inhibit different members of this family. We are also collaborating with medicinal chemists from Sloan-Kettering to design next generation inhibitors that may soon be used in clinical trials.

Dr. Gewirth's work is supported by a grant, "Structure and Regulation of hsp 90 Chaperones", from the National Cancer Institute.
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