title: Discovery of a broad spectrum antiproliferative agent with selectivity for DDR1 kinase: cell line-based assay, kinase panel, molecular docking, and toxicity studies.
abstract: 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.
authors: a Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST) , Seoul , South Korea .|b Department of Biological Chemistry , Korea University of Science and Technology (UST) , Daejeon , South Korea .
authors: Ahmed
authors: A
authors: Elkamhawy
authors: a Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST) , Seoul , South Korea .
authors: Jung-Eun
authors: JE
authors: Park
authors: c Center of Neuromedicine, Korea Institute of Science and Technology (KIST) , Seoul , South Korea .|d Department of Biotechnology , Yonsei University , Seoul , South Korea , and.
authors: Nam-Chul
authors: NC
authors: Cho
authors: a Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST) , Seoul , South Korea .|b Department of Biological Chemistry , Korea University of Science and Technology (UST) , Daejeon , South Korea .|e KU-KIST Graduate School of Converging Science and Technology , Seoul , South Korea.
authors: Taebo
authors: T
authors: Sim
authors: c Center of Neuromedicine, Korea Institute of Science and Technology (KIST) , Seoul , South Korea .
authors: Ae Nim
authors: AN
authors: Pae
authors: a Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST) , Seoul , South Korea .|b Department of Biological Chemistry , Korea University of Science and Technology (UST) , Daejeon , South Korea .
authors: Eun Joo
authors: EJ
authors: Roh
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000070819:Discoidin Domain Receptor 1; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D007527:Isoenzymes; C000611338:KST9046; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D014508:Urea; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1; D020794:Receptor Protein-Tyrosine Kinases
keywords: CYP450; DDR1 kinase inhibitor; NCI panel; kinase panel; molecular docking