Early clinical development of ARQ 197, a selective, non-ATP-competitive inhibitor targeting MET tyrosine kinase for the treatment of advanced cancers

Abstract

Expression of the receptor tyrosine kinase c-MET (MET, mesenchymal-epithelial transition factor) in many cancers, and its participation in multiple signal transduction pathways involved in malignant tumor growth, suggest a wide therapeutic potential for MET inhibition in human cancer. Here we describe the discovery and early clinical development of ARQ 197, a novel, selective, non-ATP-competitive inhibitor of MET. Phase I studies demonstrate that ARQ 197 has a predictable pharmacokinetics and favorable safety profile, making it a potentially ideal partner for combination with cytotoxic chemotherapies and targeted anticancer agents. Results from phase I and phase II trials demonstrate preliminary evidence of anticancer activity. New data from a global phase II randomized trial comparing a combination of ARQ 197 plus erlotinib with erlotinib/placebo, in endothelial growth factor receptor inhibitor-naïve patients with locally advanced/metastatic non-small cell lung cancer, demonstrate improvement in progression-free and overall survival with combined therapy. Results were especially pronounced for patients with non-squamous lung cancer histologies, and in particular molecularly defined subgroups including KRAS mutations. These and other data from ARQ 197 clinical trials in hepatocellular, germ-cell, pancreatic (in combination with gemcitabine), and colorectal (in combination with cetuximab and irinotecan) cancers further highlight the potential role of ARQ 197 in existing and emerging anticancer therapeutic regimens.

Figure 1.

Schematic representation of HCG/MET signaling pathway [3]. Activation of MET results in the recruitment of scaffolding proteins such as Gab1 and Grb2, which activate Shp2, Ras, and ERK/MAPK. Abbreviations: ERK/MAPK, extracellular signal–regulated kinase/mitogen-activated protein kinase; Gab1, growth factor receptor–bound protein 2 (Grb2)-associated binder 1; HGF/SF, hepatocyte growth factor/scatter factor; MET, mesenchymal-epithelial transition factor; Pak, p21-activated protein kinase; PI3K, phosphatidylinositol 3-kinase; PKB, protein kinase B; Shp2, SH2 domain–containing protein tyrosine phosphatase 2; SH2, Src-homology-2; Sos, son-of-sevenless; α and β, subunits of the receptor that are present after proteolytic cleavage. Adapted by permission from Macmillan Publishers Ltd. Birchmeier C, Birchmeier W, Gherardi E et al. Metastasis, motility and more. Nat Rev Mol Cell Biol 2003;4:915–925.

Figure 2.

Chemical structure of ARQ 197 [18].

Figure 3.

Kinase specificity of ARQ 197 [18]. The inhibitory effect of ARQ 197 was profiled against 230 human kinases. The size of the red circles on the kinome tree are proportional to the potency determined by repeat dose-response follow-up inhibition studies against the top five kinases inhibited by ARQ 197. Abbreviations: IC50, 50% inhibitory concentration; K_i, inhibitory constant; MET, mesenchymal-epithelial transition factor. Illustration reproduced courtesy of Cell Signaling Technology, Inc. (http://www.cellsignal.com).