Abstract 6: New chk1 inhibitor development & the feasibility of use of chk1 inhibitor with antimetabolite for NSCLC

Abstract

Abstract DNA damaging anticancer agents activate checkpoints that stop the cell cycle to prevent additional DNA replication & mitosis until damaged region has been repaired. One of the important regulatory proteins activated in DNA damage response pathway is Checkpoint kinase 1 (Chk1). Therefore, Chk1 inhibitors have emerged as promising new therapeutics for cancer. In order to find novel Chk1 inhibitor, we have conducted a structure based virtual screening. Several small molecules have shown 75 - 100 % inhibition of Chk1 in the binding affinity assay. Combined with the results of kinase assay with ATP & mechanism based cell assay, hit candidates has been led. Lung cancer is the leading cause of cancer related deaths in Korea. About 85 % of lung cancer is non-small cell lung carcinoma (NSCLC) worldwide. Chemotherapy for NSCLC is often regarded ineffective. To test the feasibility of Chk1 inhibitor to sensitize antimetabolite in NSCLC, growth inhibition induced by gemcitabine plus MK8776 was assessed in A549 & H1129 cells. These cells are insensitive to the MK8776 when treated as a single agent (IC50 >10 μM). In contrast, MK8776 reduced the concentration of gemcitabine required to inhibit H1299 or A540 cell growth by almost 3-30 fold or 6-15 fold, respectively, depending on the concentration used. These results would imply the potential clinical utility of Chk1 inhibitor as an adjuvant for antimetabolite such as gemcitabine for NSCLC. Further studies to evaluate the effectiveness of Chk1 inhibitor including new molecules would be warranted in additional preclinical and clinical settings. [The chemical library used in this study was kindly provided by Korea Chemical Bank & KIST. This study was supported by a grant (2015R1D1A1A01057014) from the National Research Foundation of Korea.] Citation Format: Injae Chung. New chk1 inhibitor development & the feasibility of use of chk1 inhibitor with antimetabolite for NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 6. doi:10.1158/1538-7445.AM2017-6