Targeting endogenous inhibitors of apoptosis: Opportunities for the treatment of cancer, stroke and MS

It is now well established that cellular suicide (apoptosis or programmed cell death) is an essential part of the maintenance of homeostasis and survival of multicellular organisms. Apoptosis is central to a number of physiological cellular processes, from host defense against viral infections to the sculpting of organs and tissues during embryonic development. Equally, or perhaps even more, important is the role of apoptosis in the pathogenesis of many human diseases.

Apoptosis stimulators have emerged as key targets for the control of cancer. This therapeutic class has, however, remained predominantly experimental and of the 100 or so molecules in development as apoptosis agonists, approaching 70% of these remain in preclinical development. The low rate of clinical entry associated with these molecules is related to lack of specificity, low efficacy and/or susceptibility to drug resistance. These issues are being addressed as our understanding of the field evolves, and as a result, the identification and exploitation of new targets remains a considerable focus of attention - indeed the number of pro-apoptotic molecules in preclinical development has risen by about 10-fold since 1995.

The uncontrolled rate of cellular death can also have dire consequences - too much cell death is often associated with the destruction of healthy cells and tissues as exemplified in neurodegenerative disorders, autoimmune disease and cardiovascular diseases. The development of strategies aimed at reducing apoptosis is therefore receiving growing interest.

It therefore follows that the tight control of the apoptotic machinery is absolutely critical for cellular survival. Indeed, several decades of research into programmed cell death have identified a large number of genes and pathways that control and influence the progression of apoptosis from the initial death trigger to the final demise of the cell. One approach to the therapeutic control of apoptosis is to activate of mimic proapoptotic agents. Alternatively a number of companies have been involved in targeting endogenous inhibitors of apoptosis, notably those from the Bcl-2 gene family. As the process of apoptosis has become better characterized it has become clear that two distinct but convergent pathways exist in the cell - the extrinsic pathway and the intrinsic pathway. Whereas the Bcl-2 proteins can block only the intrinsic pathway, members of a newer family, the IAPs ("Inhibitor of Apoptosis Proteins") can block both and hence targeting this family can offer tighter control over apoptosis. Furthermore members of the IAP family such as survivin and XIAP are highly expressed in cancers but present at much lower levels if at all in adult differentiated tissue. Targeting this family therefore offers high degrees of specificity and efficacy, characteristics that are lacking in many earlier approaches to apoptosis.

Considering the therapeutic potential of targeting the IAP family, LeadDiscovery in collaboration with Martin Holcik from the University of Ottawa has produced a full overview of this family. This dossier offers a general introduction into the apoptosis pathway and proceeds to give a detailed characterization of the various IAPs including an account of their involvement in apoptosis, their regulation and data supporting their pathophysiological role in relevant disease states. This report also describes data supporting the therapeutic activity of molecules designed to modulate IAP activity and strategies may allow improved targeting of this family.

In order to gain an insight into pharmaceutical activity within the IAP field this report lists all molecules in development as modulators of apoptosis profiling those which are at clinical stages of advancement. In addition recent patent activity surrounding the IAP family is identified. The commercial rewards surrounding apoptosis are immense and this report therefore describes the current and future apoptosis market.

In summary, this report offers a comprehensive analysis of the cellular biology, therapeutic activity and pharmaceutical potential of this recently emerging target. The reader will be able to form a clear strategy for target identification and the competition that therapeutic candidates are likely to face.