SOMG-833, a Novel Selective c-MET Inhibitor, Blocks c-MET–Dependent Neoplastic Effects and Exerts Antitumor Activity

Zhang, Haotian; Wang, Lu; Ai, Jing; Chen, Yi; He, Changyan; Ji, Yinchun; Huang, Min; Yang, Jingyu; Zhang, Ao; Ding, Jian; Geng, Meiyu

doi:10.1124/jpet.114.214817

Cited by 5 publications

(6 citation statements)

References 40 publications

(45 reference statements)

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“…In GTL‐16 and EBC‐1 cell lines, we observed downregulation of CDK2 Y15 (Table ), a phosphopeptide mapped also to CDK1 and CDK3, possibly due to downregulation of the CDK2 protein levels in EBC‐1, but not in GTL‐16 [Fig. C and previously reported (Zhang et al ., 2014)]. Modulation of CDK activity was further attested by downregulation of STMN1 S25 (Fig.…”

Section: Resultsmentioning

confidence: 86%

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Deciphering MET‐dependent modulation of global cellular responses to DNA damage by quantitative phosphoproteomics

et al. 2020

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Increasing evidence suggests that interference with growth factor receptor tyrosine kinase (RTK) signaling can affect DNA damage response (DDR) networks, with a consequent impact on cellular responses to DNA-damaging agents widely used in cancer treatment. In that respect, the MET RTK is deregulated in abundance and/or activity in a variety of human tumors. Using two proteomic techniques, we explored how disrupting MET signaling modulates global cellular phosphorylation response to ionizing radiation (IR). Following an immunoaffinity-based phosphoproteomic discovery survey, we selected candidate phosphorylation sites for extensive characterization by targeted proteomics focusing on phosphorylation sites in both signaling networks. Several substrates of the DDR were confirmed to be modulated by sequential MET inhibition and IR, or MET inhibition alone. Upon combined treatment, for two substrates, NUMA1 S395 and CHEK1 S345, the gain and loss of phosphorylation, respectively, were recapitulated using invivo tumor models by immunohistochemistry, with possible utility in future translational research. Overall, we have corroborated phosphorylation sites at the intersection between MET and the DDR signaling networks, and suggest that these represent a class of proteins at the interface between oncogene-driven proliferation and genomic stability.Abbreviations ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia and Rad3-related protein; CDK, cell cycle-dependent kinase; CHEK1, checkpoint kinase 1; CHEK2, checkpoint kinase 2; DDA, DNA-damaging agent; DDR, DNA damage response; DNA-PKcs, catalytic subunit of the DNA-dependent protein kinase

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Section: Resultsmentioning

confidence: 86%

“…B) (Factor et al ., 2010; Rebouissou et al ., 2017). Thus, given that MET inhibition leads to cell cycle arrest in these cells (Medova et al ., 2010; Zhang et al ., 2014), DDR signaling may be modulated also indirectly, via kinase activities involved in cell cycle (e.g., CDKs) and cellular growth (e.g., RSKs).…”

Section: Resultsmentioning

confidence: 99%

Deciphering MET‐dependent modulation of global cellular responses to DNA damage by quantitative phosphoproteomics

et al. 2020

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“…As consequence, treating the MET-amplified cell lines with HGF does not further increase their migration. HGF-induced MET stimulation has also been shown to be involved in angiogenesis, especially in tumors, and HGF stimulation of HUVECs results in their proliferation (40,41). To investigate the potential effect of Sym015 on the proliferation of HUVECs, GFP-transfected HUVECs were incubated with single antibodies, Sym015, and/or HGF.…”

Section: Migration and Angiogenesismentioning

confidence: 99%

Simultaneous Targeting of Two Distinct Epitopes on MET Effectively Inhibits MET- and HGF-Driven Tumor Growth by Multiple Mechanisms

Grandal

Havrylov

Poulsen

et al. 2017

Molecular Cancer Therapeutics

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Increased MET activity is linked with poor prognosis and outcome in several human cancers currently lacking targeted therapies. Here, we report on the characterization of Sym015, an antibody mixture composed of two humanized IgG antibodies against nonoverlapping epitopes of MET. Sym015 was selected by high-throughput screening searching for antibody mixtures with superior growth-inhibitory activity against MET-dependent cell lines. Synergistic inhibitory activity of the antibodies comprising Sym015 was observed in several cancer cell lines harboring amplified locus and was confirmed Sym015 was found to exert its activity via multiple mechanisms. It disrupted interaction of MET with the HGF ligand and prompted activity-independent internalization and degradation of the receptor. In addition, Sym015 induced high levels of CDC and ADCC The importance of these effector functions was confirmed using an Fc-effector function-attenuated version of Sym015. The enhanced effect of the two antibodies in Sym015 on both MET degradation and CDC and ADCC is predicted to render Sym015 superior to single antibodies targeting MET. Our results demonstrate strong potential for use of Sym015 as a therapeutic antibody mixture for treatment of MET-driven tumors. Sym015 is currently being tested in a phase I dose escalation clinical trial (NCT02648724). .

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“…Currently, several specific MET–TKIs, including lSOMCL-863 [123], SOMG-833 [124], Yhhu3813 [125], and BMS-777607 [126] are under evaluation in preclinical phases.…”

Section: Met Oncogenementioning

confidence: 99%

Small-Molecule Inhibitors of the Receptor Tyrosine Kinases: Promising Tools for Targeted Cancer Therapies

Hojjat‐Farsangi

2014

IJMS

188

144

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Chemotherapeutic and cytotoxic drugs are widely used in the treatment of cancer. In spite of the improvements in the life quality of patients, their effectiveness is compromised by several disadvantages. This represents a demand for developing new effective strategies with focusing on tumor cells and minimum side effects. Targeted cancer therapies and personalized medicine have been defined as a new type of emerging treatments. Small molecule inhibitors (SMIs) are among the most effective drugs for targeted cancer therapy. The growing number of approved SMIs of receptor tyrosine kinases (RTKs) i.e., tyrosine kinase inhibitors (TKIs) in the clinical oncology imply the increasing attention and application of these therapeutic tools. Most of the current approved RTK–TKIs in preclinical and clinical settings are multi-targeted inhibitors with several side effects. Only a few specific/selective RTK–TKIs have been developed for the treatment of cancer patients. Specific/selective RTK–TKIs have shown less deleterious effects compared to multi-targeted inhibitors. This review intends to highlight the importance of specific/selective TKIs for future development with less side effects and more manageable agents. This article provides an overview of: (1) the characteristics and function of RTKs and TKIs; (2) the recent advances in the improvement of specific/selective RTK–TKIs in preclinical or clinical settings; and (3) emerging RTKs for targeted cancer therapies by TKIs.

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SOMG-833, a Novel Selective c-MET Inhibitor, Blocks c-MET–Dependent Neoplastic Effects and Exerts Antitumor Activity

Cited by 5 publications

References 40 publications

Deciphering MET‐dependent modulation of global cellular responses to DNA damage by quantitative phosphoproteomics

Deciphering MET‐dependent modulation of global cellular responses to DNA damage by quantitative phosphoproteomics

Simultaneous Targeting of Two Distinct Epitopes on MET Effectively Inhibits MET- and HGF-Driven Tumor Growth by Multiple Mechanisms

Small-Molecule Inhibitors of the Receptor Tyrosine Kinases: Promising Tools for Targeted Cancer Therapies

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