ABSTRACT
This chapter discusses selected agents that are designed to target and modulate the activities of tyrosine kinases (TKs) other than Bcr-Abl, FLT-3, and c-KIT. Src family proteins are nonreceptor protein TKs that represent the cellular forms of the prototypical transforming protein produced by the Rous sarcoma virus. Cell signaling pathways are tightly regulated by the transfer of phosphate from adenosine triphosphate (ATP) to tyrosine residues on substrate proteins in reactions catalyzed by TK enzymes. Radicicol is a macrocyclic antifungal antibiotic, which is chemically distinct from the benzoquinone ansamycins antibiotic family, but nonetheless targets the ATP/ADP-binding site in the amino terminus of Hsp90, with resultant inhibition of ATPase activity and degradation of Hsp90 client proteins. Novobiocin and structurally related compounds, chlorobiocin and coumermycin Al, are being evaluated as alternative Hsp90 inhibitors. The ability to block the prosurvival activities of Hsp90 is a provocative concept that is being tested clinically.
