Selective inhibition of ADAM metalloproteases as a novel approach for modulating ErbB pathways in cancer.
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.
Fridman
Jordan S
JS
Drug Discovery, Incyte Corporation, Wilmington, DE 19880, USA. jfridman@incyte.com
Caulder
Eian
E
Hansbury
Michael
M
Liu
Xiangdong
X
Yang
Genjie
G
Wang
Qian
Q
Lo
Yvonne
Y
Zhou
Bin-Bing
BB
Pan
Maxwell
M
Thomas
Sufi M
SM
Grandis
Jennifer R
JR
Zhuo
Jincong
J
Yao
Wenqing
W
Newton
Robert C
RC
Friedman
Steven M
SM
Scherle
Peggy A
PA
Vaddi
Kris
K
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
D018739:Oncogene Proteins v-erbB; D051722:ADAM Proteins