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

Ahmed Elkamhawy, Jung Eun Park, Nam Chul Cho, Taebo Sim, Ae Nim Pae, Eun Joo Roh

Research output: Contribution to journalArticle

7 Citations (Scopus)

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 GI50 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 IC50 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.

Original languageEnglish
Pages (from-to)158-166
Number of pages9
JournalJournal of Enzyme Inhibition and Medicinal Chemistry
Volume31
Issue number1
DOIs
Publication statusPublished - 2016 Jan 2

Fingerprint

Phosphotransferases
Cell Line
Quinazolines
Molecular Models
National Cancer Institute (U.S.)
KST9046
Tumor Cell Line
Antineoplastic Agents
Inhibitory Concentration 50
Urea
Protein Isoforms
Enzymes
Proteins

Keywords

  • CYP450
  • DDR1 kinase inhibitor
  • kinase panel
  • molecular docking
  • NCI panel

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology

Cite this

Discovery of a broad spectrum antiproliferative agent with selectivity for DDR1 kinase : Cell line-based assay, kinase panel, molecular docking, and toxicity studies. / Elkamhawy, Ahmed; Park, Jung Eun; Cho, Nam Chul; Sim, Taebo; Pae, Ae Nim; Roh, Eun Joo.

In: Journal of Enzyme Inhibition and Medicinal Chemistry, Vol. 31, No. 1, 02.01.2016, p. 158-166.

Research output: Contribution to journalArticle

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