Identification of a Novel Recepteur d'Origine Nantais/c-Met Small-Molecule Kinase Inhibitor with Antitumor Activity In vivo

Abstract

Recepteur d'origine nantais (RON) is a receptor tyrosine kinase closely related to c-Met. Both receptors are involved in cell proliferation, migration, and invasion, and there is evidence that both are deregulated in cancer. Receptor overexpression has been most frequently described, but other mechanisms can lead to the oncogenic activation of RON and c-Met. They include activating mutations or gene amplification for c-Met and constitutively active splicing variants for RON. We identified a novel inhibitor of RON and c-Met, compound I, and characterized its in vitro and in vivo activities. Compound I selectively and potently inhibited the kinase activity of RON and c-Met with IC 50 s of 9 and 4 nmol/L, respectively. Compound I inhibited hepatocyte growth factormediated and macrophage-stimulating protein-mediated signaling and cell migration in a dose-dependent manner. Compound I was tested in vivo in xenograft models that either were dependent on c-Met or expressed a constitutively active form of . Compound I caused complete tumor growth inhibition in NIH3T3 TPR-Met and U-87 MG xenografts but showed only partial inhibition in HT-29 xenografts. The effect of compound I in HT-29 xenografts is consistent with the expression of the activating b-Raf V600E mutation, which activates the mitogen-activated protein kinase pathway downstream of RON. Importantly, tumor growth inhibition correlated with the inhibition of c-Met-dependent and RON-dependent signaling in tumors. Taken together, our results suggest that a small-molecule dual inhibitor of RON/c-Met has the potential to inhibit tumor growth and could therefore be useful for the treatment of patients with cancers where RON and/or c-Met are activated.

Synergistic Activities of MET/RON Inhibitor BMS-777607 and mTOR Inhibitor AZD8055 to Polyploid Cells Derived from Pancreatic Cancer and Cancer Stem Cells

“…BMS-777607 is a MET superfamily inhibitor with a high specificity to RON at the enzymatic IC 50 of 1.8 nmol/L (16). This is the highest inhibitory IC 50 value observed among various TKIs showing RON inhibitory activity (14)(15)(16). The other targets of BMS-777607 include MET (IC 50 , 3.9 nmol/L), Tyro-3 (IC 50 , 4.3 nmol/L), and Mer (IC 50 , 14.0 nmol/L; ref.…”

“…This is the highest inhibitory IC 50 value observed among various TKIs showing RON inhibitory activity (14)(15)(16). The other targets of BMS-777607 include MET (IC 50 , 3.9 nmol/L), Tyro-3 (IC 50 , 4.3 nmol/L), and Mer (IC 50 , 14.0 nmol/L; ref. 16).…”

“…Both tyrosine kinase inhibitors (TKI) and therapeutic monoclonal antibodies (mAb) have been tested in preclinical models (7,14). Moreover, anti-RON antibodies have been used as a drug delivery method to improve chemotherapeutic efficacy (13).…”

“…Moreover, anti-RON antibodies have been used as a drug delivery method to improve chemotherapeutic efficacy (13). Currently, several TKIs, including PHA665752, compound-I, and BMS-777607, that target RON signaling have been characterized in a preclinical model (4)(5)(6)(14)(15)(16). BMS-777607 is a MET superfamily inhibitor with a high specificity to RON at the enzymatic IC 50 of 1.8 nmol/L (16).…”

RON - The Con in Colorectal Carcinoma

“…Several SMI such as quinoline based compound from Amgen, BMS-777607 from BristolMyers Squib and compound I have been described to inhibit RON/cMet kinase [64]. Compound I has been shown to result in partial inhibition of HT-29 colon xenografts [65]. However the high sequence similarity between the catalytic domains of these kinases makes the design of specific inhibitors challenging [5].…”