Altering the Apoptotic Network in Cancer: A Promising Therapeutic Approach

Since the discovery of the first apoptotic regulator in 1984 it has been demonstrated that networks promoting cell survival are a key component of many cancers that are resistant to treatment. Promising results from our work towards overcoming this resistance by selectively antagonizing specific survival pathways will be discussed. The presentation will highlight potential therapeutic benefit of antagonizing members of the Inhibitor of Apoptosis proteins (IAP) as well as members of the B-cell lymphoma-2 (BCL-2) family of protein.

The discovery and development of small molecules that disrupt protein-protein interactions pose considerable challenges. Amongst these, the pro-survival IAP and BCL-2 proteins represent highly attractive targets for drug discovery and development since their overexpression is closely associated with tumor progression and maintenance. Developing well-validated compounds that display potent target modulation of pro-survival BCL 2 proteins is therefore an attractive and novel strategy for treating cancers. Highly selective inhibition of pro-survival proteins may well be advantageous in the clinic since on-target side-effects should be curtailed.

Here, we describe the discovery of several completely novel series of small molecules that selectively target the IAP and select members of the BCL-2 proteins (BCL-2 and BCL-XL). Our work, guided by extensive structural information and supported by biochemical studies, illustrates the progression from a low-micromolar screening hit to a potent and selective nanomolar and sub-nanomolar compounds.