SOMCL-863, a novel, selective and orally bioavailable small-molecule c-Met inhibitor, exhibits antitumor activity both in vitro and in vivo

Lu Wang; Jing Ai; Yanyan Shen; Haotian Zhang; Xia Peng; Min Huang; Ao Zhang; Jian Ding; Meiyu Geng

doi:10.1016/j.canlet.2014.05.012

SOMCL-863, a novel, selective and orally bioavailable small-molecule c-Met inhibitor, exhibits antitumor activity both in vitro and in vivo

Cancer Lett. 2014 Aug 28;351(1):143-50. doi: 10.1016/j.canlet.2014.05.012. Epub 2014 May 28.

Authors

Lu Wang¹, Jing Ai¹, Yanyan Shen¹, Haotian Zhang², Xia Peng¹, Min Huang¹, Ao Zhang³, Jian Ding⁴, Meiyu Geng⁵

Affiliations

¹ Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
² Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China; Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China.
³ CAS Key Laboratory of Receptor Research, and Synthetic Organic & Medicinal Chemistry Laboratory (SOMCL), Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
⁴ Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China. Electronic address: [email protected].
⁵ Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China. Electronic address: [email protected].

PMID: 24880078
DOI: 10.1016/j.canlet.2014.05.012

Abstract

Deregulation of HGF/c-Met signaling and its driven neoplastic phenotype are associated with a variety of human malignancies. We herein reported SOMCL-863 as a novel selective c-Met inhibitor which effectively abrogated c-Met signaling pathways, thereby leading to substantial impairment of c-Met-dependent cell proliferation, migration, invasion, cell scattering and invasive growth. In EBC-1 and NCI-H1993 xenografts, SOMCL-863 exerted significant anti-tumor efficacy through anti-proliferative effects and antiangiogenic mechanisms, including reduction of tumor cell proliferation and reductions of microvessel density and secretion of proangiogenic factor IL-8. Together with the optimal pharmacokinetic properties, SOMCL-863 is a promising candidate worthy for further evaluation as a treatment of c-Met-driven human cancers.

Keywords: Angiogenesis; Cancer; Receptor tyrosine kinase; SOMCL-863; c-Met.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Animals
Antineoplastic Agents / administration & dosage*
Antineoplastic Agents / pharmacokinetics
Biological Availability
Cell Line, Tumor
Female
Hepatocyte Growth Factor / physiology
Humans
Inhibitory Concentration 50
Mice
Mice, Nude
Neovascularization, Pathologic / drug therapy
Proto-Oncogene Proteins c-met / antagonists & inhibitors*
Proto-Oncogene Proteins c-met / metabolism
Quinolines / administration & dosage*
Quinolines / pharmacokinetics
Signal Transduction
Tumor Burden / drug effects
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
HGF protein, human
Quinolines
SOMCL-863
Hepatocyte Growth Factor
Proto-Oncogene Proteins c-met