Wednesday, February 5, 2014
Sympathy for the Devil: Taking IAP Antagonists from Research to the Clinic
Christopher S. Straub, Ph.D., Novartis
Since the first description of apoptosis was proposed in the 1970's, this pathway of programmed cell death has held great promise in the fight against many diseases including autoimmune diseases and cancer. The following three decades of research provided many possible biological targets within the apoptosis signaling network that could be manipulated to promote or hinder this process and offer possible therapies for these diseases. Fourteen years ago, the inhibitor of apoptosis proteins (IAPs) emerged as a promising candidate to target. Despite being a protein-protein interaction target, several academic and industrial groups initiated efforts to develop small molecule agonists against these 'nefarious' proteins that theoretically kept disease cells alive by inhibiting caspases. Novartis, and others, have now produced small molecules to test this theory in animal models and human subjects. This presentation will detail the evolution of our understanding of these proteins and the development of orally bioavailable small molecules targeting the IAP proteins, culminating in the discovery of the Novartis clinical compound LCL161. The presentation will also offer some perspectives on targeting PPI's and on the current state of targeting apoptosis signaling to treat proliferative diseases.