Evaluation of a multi-kinase inhibitor KRC-108 as an anti-tumor agent in vitro and in vivo.

Abstract

Kinases have been studied as potential cancer targets because they play important roles in the cellular signaling of tumors. A number of small molecules targeting kinases are prescribed in clinics and many kinase inhibitors are being evaluated in the clinical phase. Previously, we discovered a series of aminopyridines substituted with benzoxazole as orally active c-Met kinase inhibitors. One of the compounds, KRC-108, has been evaluated as an anti-cancer agent in vitro and in vivo. A kinase panel assay exhibited that KRC-108 is a potent inhibitor of Ron, Flt3 and TrkA as well as c-Met. Moreover, KRC-108 inhibited oncogenic c-Met M1250T and Y1230D more strongly than wild type c-Met. The anti-proliferative activity of KRC-108 was measured by performing a cytotoxicity assay on a panel of cancer cell lines. The GI(50) values (i.e., 50% inhibition of cell growth) for KRC-108 ranged from 0.01 to 4.22 μM for these cancer cell lines. KRC-108 was also effective for the inhibition of tumor growth in human HT29 colorectal cancer and NCI-H441 lung cancer xenograft models in athymic BALB/c nu/nu mice. This molecule should serve as a useful lead for inhibitors targeting kinases and may lead to new therapeutics for the treatment of cancer.

• Authors: Sun-Young Han, Chong Ock Lee, Sung-Hoon Ahn, Mi-Ok Lee, So-Young Kang, Hyuk-Jin Cha, Sung Yun Cho, Jae Du Ha, Jae Wook Ryu, Heejung Jung, Hyoung Rae Kim, Jong Sung Koh, Jongkook Lee
• Journal: Investigational new drugs (Invest New Drugs) Vol. 30 Issue 2 Pg. 518-23 (Apr 2012) ISSN: 1573-0646 [Electronic] United States
• PMID: 21080208 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aminopyridines
• Antineoplastic Agents
• Benzoxazoles
• Cytochrome P-450 Enzyme Inhibitors
• KRC-108
• Protein Kinase Inhibitors
• Cytochrome P-450 Enzyme System
• Proto-Oncogene Proteins c-met
• RON protein
• Receptor Protein-Tyrosine Kinases
• Receptor, trkA
• fms-Like Tyrosine Kinase 3

Topics

• Administration, Oral
• Aminopyridines (administration & dosage, pharmacokinetics, pharmacology)
• Animals
• Antineoplastic Agents (administration & dosage, pharmacokinetics, pharmacology)
• Benzoxazoles (administration & dosage, pharmacokinetics, pharmacology)
• Cell Proliferation (drug effects)
• Colorectal Neoplasms (drug therapy, enzymology, pathology)
• Cytochrome P-450 Enzyme Inhibitors
• Cytochrome P-450 Enzyme System (metabolism)
• Dose-Response Relationship, Drug
• Female
• HT29 Cells
• Humans
• Inhibitory Concentration 50
• Lung Neoplasms (drug therapy, enzymology, pathology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Protein Kinase Inhibitors (administration & dosage, pharmacokinetics, pharmacology)
• Proto-Oncogene Proteins c-met (antagonists & inhibitors, metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptor Protein-Tyrosine Kinases (antagonists & inhibitors, metabolism)
• Receptor, trkA (antagonists & inhibitors, metabolism)
• Time Factors
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays
• fms-Like Tyrosine Kinase 3 (antagonists & inhibitors, metabolism)