Discovery of a broad spectrum antiproliferative agent with selectivity for DDR1 kinase: cell line-based assay, kinase panel, molecular docking, and toxicity studies

• Published in: Journal of enzyme inhibition and medicinal chemistry Vol. 31; no. 1; pp. 158 - 166
• Main Authors: Elkamhawy, Ahmed, Park, Jung-eun, Cho, Nam-Chul, Sim, Taebo, Pae, Ae Nim, Roh, Eun Joo
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 02.01.2016
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; CYP450; DDR1 kinase inhibitor; Discoidin Domain Receptor 1; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Humans; Isoenzymes - antagonists & inhibitors; Isoenzymes - metabolism; kinase panel; molecular docking; Molecular Docking Simulation; Molecular Structure; NCI panel; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Quinazolines - chemical synthesis; Quinazolines - chemistry; Quinazolines - pharmacology; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - metabolism; Structure-Activity Relationship; Urea - analogs & derivatives; Urea - chemical synthesis; Urea - chemistry; Urea - pharmacology; DDR1 kinase inhibitor; NCI panel; molecular docking; CYP450; kinase panel
• ISSN: 1475-6366; 1475-6374
• DOI: 10.3109/14756366.2015.1004057

Herein, we report compound KST9046, a new agent possessing quinazoline-urea scaffold. Preliminary biological evaluation done by the National Cancer Institute (NCI), USA, showed a great inhibitory effect of KST9046 over the 60 cell-line tumor panel. Accordingly, it was selected for a dose-response assay; a broad spectrum antiproliferative activity with GI 50 ranging from 1.3 to 3.9 µM was exerted. To explore a potential kinase inhibitory effect, KST9046 was applied at a single dose of 10 µM against a kinase panel of 347 different enzymes representing >50% of the predicted human protein kinome. Interestingly, selective inhibition of 76% was observed on DDR1 kinase. Further, KST9046 showed an IC 50 value of 4.38 µM for DDR1. A molecular docking model presented KST9046 as a potential type III inhibitor for DDR1 kinase with an allosteric mode of interaction, which may offer an explanation for its selectivity. As further investigation, CYP450 assay was carried out for KST9046, it showed a promising toxicity profile against four different isoforms. Based on these findings, KST9046 can be further evaluated as a promising safe new hit for the development of broad spectrum anticancer agents with a selectivity for DDR1 kinase.