Fragment-Based
Drug Discovery Targeting Inhibitor
of Apoptosis Proteins: Discovery of a Non-Alanine Lead Series with
Dual Activity Against cIAP1 and XIAP
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Abstract
Inhibitor
of apoptosis proteins (IAPs) are important regulators
of apoptosis and pro-survival signaling pathways whose deregulation
is often associated with tumor genesis and tumor growth. IAPs have
been proposed as targets for anticancer therapy, and a number of peptidomimetic
IAP antagonists have entered clinical trials. Using our fragment-based
screening approach, we identified nonpeptidic fragments binding with
millimolar affinities to both cellular inhibitor of apoptosis protein
1 (cIAP1) and X-linked inhibitor of apoptosis protein (XIAP). Structure-based
hit optimization together with an analysis of protein–ligand
electrostatic potential complementarity allowed us to significantly
increase binding affinity of the starting hits. Subsequent optimization
gave a potent nonalanine IAP antagonist structurally distinct from
all IAP antagonists previously reported. The lead compound had activity
in cell-based assays and in a mouse xenograft efficacy model and represents
a highly promising start point for further optimization