Facilitating the development of anticancer drugs
May 12, 2003
Structural biologists from 捆绑SM社区 have discovered a mechanism that sheds light on how certain proteins regulate programmed cell death (also known as apoptosis). In a recently published paper, Professor Kalle Gehring and Dr Alexei Denisov from 捆绑SM社区's Department of Biochemistry, in collaboration with scientists from Gemin X Biotechnologies, Inc., have shown that cell death regulator Bcl-W proteins carry a protective structural element that is displaced when these proteins associate with pro cell death partners. The findings, published online on March 21, 2003 in the Journal of Biological Chemistry and the April 1, 2003 issue of the prestigious EMBO Journal, are expected to advance the discovery of novel drugs to treat cancer, based on the regulation of cell death.
Supporting observations on the structure of Bcl-W were simultaneously reported by Dr Catherine Day from the Department of Biochemistry at University of Otago, New Zealand, in collaboration with Drs Mark Hinds and David Huang from the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia.
Cancer is characterized by the coincidence of a number of different factors affecting cells and tissue. These include limitless replication potential, auto-generation of growth signals, lack of sensitivity to anti-growth signals, angiogenesis, metastasis and apoptosis resistance. While the latter is the disease's most devastating feature, it also represents the greatest therapeutic opportunity, since overcoming resistance to death signals would allow cancer cells to self-destruct, eliminating the threat posed by other contributing factors.
Bcl-W is one of the five members of the Bcl-2 family of apoptotic proteins whose overexpression in cells leads to apoptosis resistance and the onset of cancer. In response to a death signal, Bcl-W proteins migrate from the cytoplasm to the surface of cellular mitochondria and block BH3-only pro-death proteins, thereby interrupting the cell death process. The Bcl-W/BH3 association requires a change in the structure of the Bcl-W proteins that involves removal of the protective structural element to expose a groove in the protein surface in which the BH3 domain inserts itself. Drugs that could disrupt the Bcl-W/BH3 interaction by blocking Bcl-W would represent a significant advance in cancer therapy since they could remove a barrier to apoptosis, leaving pro-death proteins to do their work.
The present discovery has important implications for the development of therapeutics that mimic the action of the BH3 peptide: it suggests an ideal drug targeting this system should be able to induce structural changes in Bcl-W and lodge itself in the groove on the protein surface. Compounds functioning through this dual mechanism would represent a novel class of therapeutics with significant potential as anticancer drugs.
The discovery is the result of an ongoing research partnership between 捆绑SM社区 and Gemin X Biotechnologies. This intersection of basic and therapeutically relevant research illustrates the critical role 捆绑SM社区 researchers continue to play in the development of a world-class biotechnology community in the Montreal area.
Professor Gehring's laboratory focuses on the application of nuclear magnetic resonance (NMR) spectroscopy to the study of protein and nucleic acid structures. His group, comprising fifteen (15) research associates, assistants, postdoctoral fellows and students, is actively engaged in studying the process of molecular recognition in biological systems. This fundamental process governs how various parts of the cellular machinery communicate with each other to transmit signals and alter the states of a cell. Professor Gehring led two Canada Foundation for Innovation grants for the establishment of a Quebec/Eastern Canada Regional NMR Centre comprising five NMR spectrometers at 捆绑SM社区 and the Universit茅 de Montr茅al, including a new 800 MHz NMR.
Gemin X Biotechnologies Inc., established in 1998 by 捆绑SM社区 professors Philip Branton and Gordon Shore, is a Montreal-based biotech company focusing on the modulation of programmed cell death to discover novel cancer therapeutics. The company's lead anticancer agent acts as a pan-inhibitor of anti-apoptotic Bcl-2 proteins and is expected to enter the clinic at the end of 2003. Since its inception, Gemin X has maintained close ties to the University through various licensing agreements and research collaborations.
