Targeting endogenous inhibitors of apoptosis: Therapeutic Opportunities

E Sussex, UK 15th January 2003 --- New LeadDiscovery Dossier. 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. 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 or 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. This DiscoveryDossier offer a full overview of the IAP family and its therapeutic potential. This is placed in the context of an analysis of pharmaceutical activity within the apoptosis field.

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