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

doi:10.3109/14756366.2015.1004057

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

28 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 language	English
Pages (from-to)	158-166
Number of pages	9
Journal	Journal of Enzyme Inhibition and Medicinal Chemistry
Volume	31
Issue number	1
DOIs	https://doi.org/10.3109/14756366.2015.1004057
Publication status	Published - 2016 Jan 2

Bibliographical note

Funding Information:
We would like to thank the National Cancer Institute (NCI), Bethesda, MD, USA, for performing the anticancer testing over the cell lines. We also appreciate Dr Haiching Ma from Reaction Biology Corporation for kinase profile screening. The authors have declared no conflict of interest. This research was supported by a grant (NRF-2011-0028676) from the creative/challenging research program of National Research Foundation of Korea.

Publisher Copyright:
© 2015 Korea Institute of Science and Technology. Published by Taylor & Francis.

Keywords

CYP450
DDR1 kinase inhibitor
NCI panel
kinase panel
molecular docking

ASJC Scopus subject areas

Pharmacology
Drug Discovery

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3109/14756366.2015.1004057

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

Research output: Contribution to journal › Article › peer-review

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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.",

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note = "Funding Information: We would like to thank the National Cancer Institute (NCI), Bethesda, MD, USA, for performing the anticancer testing over the cell lines. We also appreciate Dr Haiching Ma from Reaction Biology Corporation for kinase profile screening. The authors have declared no conflict of interest. This research was supported by a grant (NRF-2011-0028676) from the creative/challenging research program of National Research Foundation of Korea. Publisher Copyright: {\textcopyright} 2015 Korea Institute of Science and Technology. Published by Taylor \& Francis.",

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AU - Sim, Taebo

AU - Pae, Ae Nim

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AB - 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.

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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