title: Selective inhibition of ADAM metalloproteases as a novel approach for modulating ErbB pathways in cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Drug Discovery, Incyte Corporation, Wilmington, DE 19880, USA. jfridman@incyte.com
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Fridman
authors.forename: Eian
authors.initials: E
authors.lastname: Caulder
authors.forename: Michael
authors.initials: M
authors.lastname: Hansbury
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Liu
authors.forename: Genjie
authors.initials: G
authors.lastname: Yang
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Lo
authors.forename: Bin-Bing
authors.initials: BB
authors.lastname: Zhou
authors.forename: Maxwell
authors.initials: M
authors.lastname: Pan
authors.forename: Sufi M
authors.initials: SM
authors.lastname: Thomas
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Grandis
authors.forename: Jincong
authors.initials: J
authors.lastname: Zhuo
authors.forename: Wenqing
authors.initials: W
authors.lastname: Yao
authors.forename: Robert C
authors.initials: RC
authors.lastname: Newton
authors.forename: Steven M
authors.initials: SM
authors.lastname: Friedman
authors.forename: Peggy A
authors.initials: PA
authors.lastname: Scherle
authors.forename: Kris
authors.initials: K
authors.lastname: Vaddi
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018739:Oncogene Proteins v-erbB / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018739:Oncogene Proteins v-erbB; D051722:ADAM Proteins