Supplementary Table 1 | The biochemical, biological and pharmacological properties of tivantinib
are distinct to other MET inhibitors.
Crizotinib, PHA-665752, JNJ-38877605, DN-30 Fab
Selected based on their ability to inhibit MET tyrosine
kinase activity or to cause MET downregulation
Tivantinib
Identified in a cell-based screen for pro-apoptotic
agents
Display selective activity in MET-addicted cells
(displaying c-MET gene amplification)
Displays cytotoxic activity towards all cells regardless
of c-MET gene copy number or MET protein
expression, including cells expressing kinase-dead MET
or not expressing MET at all
Fail to inhibit the growth of cells that have become
Displays equal cytotoxicity towards MET inhibitorresistant to MET inhibition by multiple mechanisms
sensitive and MET inhibitor-resistant cells
Potently inhibit both HGF-dependent and HGFFails to inhibit either HGF-dependent or HGFindependent MET auto-phosphorylation and block
independent MET auto-phosphorylation and does not
downstream ERK-AKT signalling
block downstream AKT/ERK signalling
Cause G1 arrest of cells displaying c-MET gene
Causes G2/M arrest and apoptosis of all cells
amplification
independently of c-MET genetic status and MET
protein expression
Have no effect on microtubule stability
Interferes with microtubule polymerization
independently of the presence or absence of a
functional MET protein
Crizotinib is a dual ALK-MET small-molecule inhibitor approved for non-small-cell lung cancer. PHA-665752 is a
MET-selective small-molecule inhibitor that blocks HGF/MET-dependent biological activity in preclinical models.
JNJ-38877605 is a MET-selective small-molecule inhibitor discontinued from clinical development owing to offtarget toxic effects. DN-30 Fab is the Fab fragment of a monoclonal anti-MET antibody inducing receptor
shedding and downregulation.1,2
1
Figure 1 | The MET inhibitor herd. Basilico et al.1 and Katayama et al.2 directly compared the pharmacological
properties of tivantinib with those of other MET inhibitors including crizotinib (a dual ALK-MET tyrosine kinase
inhibitor (TKI) approved for non-small-cell lung cancer), PHA-665,752 (a preclinical MET TKI), JNJ-38877605 (a
MET TKI inhibitor discontinued from clinical development owing to off-target toxic effects), and DN-30 (a
monoclonal anti-MET antibody inducing receptor shedding and downregulation). Additional MET inhibitors not
analysed in these studies include onartuzumab (a one-armed monoclonal anti-MET antibody in phase III for nonsmall-cell lung cancer and gastric cancer) and a number of MET-selective TKIs (AMG-337, EMD-1214063,
EMD-1204831, SGX-523 and INCB28060) that are being tested in phase I in solid tumours. Additionally,
antibodies have been developed to target HGF, the high affinity ligand for MET, including rilotumumab (in
phase III for gastric cancer), ficlatuzumab (in phase II for non-small-cell lung cancer), and TAK-701 (in phase I in
solid tumours).
2