Angewandte Chemie International Edition

Cover image for Vol. 55 Issue 7

Chefredakteur: Peter Gölitz, Stellvertreter: Neville Compton, Haymo Ross

Online ISSN: 1521-3773

Associated Title(s): Angewandte Chemie, Chemistry - A European Journal, Chemistry – An Asian Journal, ChemistryOpen, ChemPlusChem, Zeitschrift für Chemie

Press Release

For full article and contact information, see Angew. Chem. Int. Ed. 2003, 42 (5), 535- 539

No. 05/2003

Euthanasia for Cells

A Molecule off the "drawing board" should restart
the disrupted cell death program in tumors

A cell's readiness to die on command is an important prerequisite for the viability of a multicellular organism. This process, called apoptosis, plays an important role in embryonic development, as well as in protection against degenerate cells. In apostosis, the cells do not just die off in an uncontrolled manner; they follow a strictly regulated program. If something goes awry in this complex control system, it can cause serious diseases: certain cancers are strongly linked to inhibited apoptosis, for example. A team working with Andrew Hamilton at Yale University in New Haven has developed a compound that can steer the tumor cell's apoptosis program back onto the right track, and may thus be the starting point for the development of a new type of medication.

The life and death of a cell depend on a properly balanced relationship between a group of proteins. For example, there are the apoptosis-promoting protein, Bak, and its counterpart, the protein Bcl-xL. When the apoptosis inhibitor Bcl-xL binds to Bak, the latter cannot play its assigned role. In certain cancer cells, far too much Bcl-xL is produced. Even if an apoptosis command reaches the cell, no apoptosis occurs because there is practically no free Bak present. Hamilton and his co-workers would like to trap the excess Bcl-xL. They were thus looking for a compound that docks onto Bcl-xL and frees the bound Bak.

The rather young field of targeted structure design helped the Yale researchers along. They were able to develop a compound as though at a drawing board; the compound's structure is modeled on those domains of the Bak protein that slip into the binding pocket of Bcl-xL upon coupling. The domains in question are wound into what is called an alpha-helix, a structural element that is quite common among proteins. Special side chains stretch out on one side of this helix, and these are responsible for the bond within the binding pocket. In place of the protein helix, the Hamilton group constructed a flat backbone from three amide-bridged, nitrogen-containing carbon rings. They attached a short side chain, comparable in characteristics and position to three of the protein side chains, onto each ring. Computer simulations show that the drawing-board compound fits perfectly nicely into the binding pocket of Bcl-xL. And in laboratory experiments, the new compound was indeed able to force the apoptosis protein Bak out of its bond to Bcl-xL.