Novel C-Met Inhibitor Suppresses the Growth of C-Met-addicted Gastric Cancer Cells

Overview

Journal BMC Cancer

Publisher Biomed Central

Specialty Oncology

Date 2016 Jan 24

PMID 26801760

Citations 17

Authors

Chi Hoon Park

Sung Yun Cho

Jae Du Ha

Heejung Jung

Hyung Rae Kim

Chong Ock Lee

In-Young Jang

Chong Hak Chae

Heung Kyoung Lee

Sang Un Choi

Affiliations

Soon will be listed here.

Abstract

Background: c-Met signaling has been implicated in oncogenesis especially in cells with c-met gene amplification. Since 20 % of gastric cancer patients show high level of c-Met expression, c-Met has been identified as a good candidate for targeted therapy in gastric cancer. Herein, we report our newly synthesized c-Met inhibitor by showing its efficacy both in vitro and in vivo.

Methods: Compounds with both triazolopyrazine and pyridoxazine scaffolds were synthesized and tested using HTRF c-Met kinase assay. We performed cytotoxic assay, cellular phosphorylation assay, and cell cycle assay to investigate the cellular inhibitory mechanism of our compounds. We also conducted mouse xenograft assay to see efficacy in vivo.

Results: KRC-00509 and KRC-00715 were selected as excellent c-Met inhibitors through biochemical assay, and exhibited to be exclusively selective to c-Met by kinase panel assay. Cytotoxic assays using 18 gastric cancer cell lines showed our c-Met inhibitors suppressed specifically the growth of c-Met overexpressed cell lines, not that of c-Met low expressed cell lines, by inducing G1/S arrest. In c-met amplified cell lines, c-Met inhibitors reduced the downstream signals including Akt and Erk as well as c-Met activity. In vivo Hs746T xenograft assay showed KRC-00715 reduced the tumor size significantly.

Conclusions: Our in vitro and in vivo data suggest KRC-00715 is a potent and highly selective c-Met inhibitor which may have therapeutic potential in gastric tumor with c-Met overexpression.

Citing Articles

Research progress on the development of hepatocyte growth factor/c-Met signaling pathway in gastric cancer: A review.

Wei W, Hong Y, Deng Y, Wang G, Qiu J, Pan F World J Gastrointest Oncol. 2024; 16(8):3397-3409.

PMID: 39171189 PMC: 11334049. DOI: 10.4251/wjgo.v16.i8.3397.

Ferroptosis regulating lipid peroxidation metabolism in the occurrence and development of gastric cancer.

Wang L, Zhang W, Qiu Y, Wang F World J Gastrointest Oncol. 2024; 16(6):2781-2792.

PMID: 38994139 PMC: 11236228. DOI: 10.4251/wjgo.v16.i6.2781.

Characterization of MET Alterations in 37 Gastroesophageal Cancer Cell Lines for MET-Targeted Therapy.

Kim J, Kim M, Hong S Int J Mol Sci. 2024; 25(11).

PMID: 38892160 PMC: 11173193. DOI: 10.3390/ijms25115975.

Patient-derived exosomes facilitate therapeutic targeting of oncogenic MET in advanced gastric cancer.

Hyung S, Ko J, Heo Y, Blum S, Kim S, Park S Sci Adv. 2023; 9(47):eadk1098.

PMID: 38000030 PMC: 10672184. DOI: 10.1126/sciadv.adk1098.

Opportunities and challenges of targeting c-Met in the treatment of digestive tumors.

Zhang Z, Li D, Yun H, Tong J, Liu W, Chai K Front Oncol. 2022; 12:923260.

PMID: 35978812 PMC: 9376446. DOI: 10.3389/fonc.2022.923260.

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