PURPOSE: ErbB receptor signaling pathways are important regulators of cell fate, 
and their dysregulation, through (epi)genetic alterations, plays an etiologic 
role in multiple cancers. ErbB ligands are synthesized as membrane-bound 
precursors that are cleaved by members of the ADAM family of zinc-dependent 
metalloproteases. This processing, termed ectodomain shedding, is essential for 
the functional activation of ErbB ligands. Recent studies suggest that elevated 
levels of ErbB ligands may circumvent the effectiveness of ErbB-targeted 
therapeutics. Here, we describe the discovery and preclinical development of 
potent, selective inhibitors of ErbB ligand shedding.
EXPERIMENTAL DESIGN: A series of biochemical and cell-based assays were 
established to identify selective inhibitors of ErbB ligand shedding. The 
therapeutic potential of these compounds was assessed in multiple in vivo models 
of cancer and matrix metalloprotease-related toxicity.
RESULTS: INCB3619 was identified as a representative selective, potent, orally 
bioavailable small-molecule inhibitor of a subset of ADAM proteases that block 
shedding of ErbB ligands. Administration of INCB3619 to tumor-bearing mice 
reduced ErbB ligand shedding in vivo and inhibited ErbB pathway signaling (e.g., 
phosphorylation of Akt), tumor cell proliferation, and survival. Further, 
INCB3619 synergized with clinically relevant cancer therapeutics and showed no 
overt or compounding toxicities, including fibroplasia, the dose-limiting 
toxicity associated with broad-spectrum matrix metalloprotease inhibitors.
CONCLUSIONS: Inhibition of ErbB ligand shedding offers a potentially novel and 
well-tolerated therapeutic strategy for the treatment of human cancers and is 
currently being evaluated in the clinic.