Combinatorial Drugs Target Cancer Cell Mitochondria

Cancer researchers have used a process of "combinatorial” drug design to create a class of small molecule compounds that kill cancer cells by entering and destroying their mitochondria. In this case, the term describes a molecule that is directed at a specific protein, Hsp90, with the combined specificity for the mitochondria of cancer cells.

Investigators from the University of Massachusetts Medical School (Worcester, USA) named their new class of drugs Gamitrinibs. The structure of a Gamitrinib is combinatorial and contains a benzoquinone ansamycin backbone derived from the Hsp90 inhibitor 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), a linker region on the C17 position, and a mitochondrial targeting moiety, either provided by one to four tandem repeats of cyclic guanidinium (Gamitrinib-G1–G4) or triphenylphosphonium (Gamitrinib–TPP-OH). By molecular dynamics simulation, the 17-AAG portion of Gamitrinib is predicted to make contacts with the Hsp90 ATPase pocket, whereas the "mitochondriotropic” guanidinium module is excluded from the binding interface, pointing outside of the ATP (adenotriphosphate)ase pocket toward the solvent. Hsp90 is a chaperone protein that controls the folding of proteins in multiple signaling networks that drive tumor development and progression.

Results published in the February 23, 2009, issue of the Journal of Clinical Investigation (JCI) revealed that Gamitrinibs accumulated in the mitochondria of human tumor cell lines where they inhibited Hsp90 activity by acting as ATPase antagonists. Unlike Hsp90 antagonists not targeted to mitochondria, Gamitrinibs exhibited a "mitochondriotoxic” mechanism of action, causing rapid tumor cell death and inhibiting the growth of xenografted human tumor cell lines in mice. Importantly, Gamitrinibs were not toxic to normal cells or tissues and did not affect Hsp90 homeostasis in cellular compartments other than mitochondria.

The combinatorial technique allowed the development of molecules that targeted a protein that controls multiple signaling pathways. Furthermore, the drugs were directed towards one specific cellular compartment in which Hsp90 is active in tumor cells' mitochondria. Treatment with these drugs effectively induced tumor cell death in mice transplanted with human tumor cell lines. Thus, the researchers concluded that, "combinatorial drug design, whereby inhibitors of signaling networks are targeted to specific cellular compartments, may prove a more effective strategy for developing anticancer drugs than targeting single signaling pathways.”

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University of Massachusetts Medical School