Novel CHK1 Inhibitor Enhances Antitumor Activity with Selected Anticancer Drugs

Scientists in the United Kingdom have made a groundbreaking discovery in the field of cancer research, developing a novel CHK1 inhibitor that has the potential to enhance antitumor activity with selected anticancer drugs in vivo. The study, led by M.I. Walton and colleagues at the Institute of Cancer Research, reveals that the compound, SAR-020106, abrogates etoposide-induced G(2) arrest and significantly enhances the cell killing of gemcitabine and SN38 in colon tumor lines in vitro and in a p53-dependent fashion.

Key Takeaways:

• SAR-020106 is an ATP-competitive, potent, and selective CHK1 inhibitor with an IC(50) of 13.3 nmol/L on the isolated human enzyme.
• The compound abrogates etoposide-induced G(2) arrest with an IC(50) of 55 nmol/L in HT29 cells.
• SAR-020106 enhances the cell killing of gemcitabine and SN38 by 3.0-to 29-fold in several colon tumor lines in vitro and in a p53-dependent fashion.
• Biomarker studies have shown that SAR-020106 inhibits cytotoxic drug-induced autophosphorylation of CHK1 at S296 and blocks the phosphorylation of CDK1 at Y15 in a dose-dependent fashion both in vitro and in vivo.
• Cytotoxic drug combinations were associated with increased gammaH2AX and poly ADP ribose polymerase cleavage consistent with the SAR-020106-enhanced DNA damage and tumor cell death.
• Irinotecan and gemcitabine antitumor activity were enhanced by SAR-020106 in vivo with minimal toxicity.

Statistics:

• SAR-020106 has an IC(50) of 13.3 nmol/L in isolated human enzyme assays.
• The compound abrogates etoposide-induced G(2) arrest with an IC(50) of 55 nmol/L in HT29 cells.
• SAR-020106 enhances the cell killing of gemcitabine and SN38 by 3.0-to 29-fold in several colon tumor lines in vitro and in a p53-dependent fashion.

Sources:

• Walton, M.I., et al. "The preclinical pharmacology and therapeutic activity of the novel CHK1 inhibitor SAR-020106." Molecular Cancer Therapeutics, 2010;9(1):89-100.
• DNA Research.