Synthesis and biological evaluation of new pyrazol-4-ylpyrimidine derivatives as potential ROS1 kinase inhibitors

Ahmed Z. Abdelazem; Mohammad M. Al-Sanea; Byung Sun Park; Hye Mi Park; Kyung Ho Yoo; Taebo Sim; Jong Bae Park; Seung Hoon Lee; So Ha Lee

doi:10.1016/j.ejmech.2014.11.023

Synthesis and biological evaluation of new pyrazol-4-ylpyrimidine derivatives as potential ROS1 kinase inhibitors

Ahmed Z. Abdelazem, Mohammad M. Al-Sanea, Byung Sun Park, Hye Mi Park, Kyung Ho Yoo, Taebo Sim, Jong Bae Park, Seung Hoon Lee, So Ha Lee

KU-KIST Graduate School of Converging Science and Technology

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

12 Citations (Scopus)

Abstract

With the aim of discovering potent and selective kinase inhibitors targeting ROS1 kinase, we designed, synthesized and screened a series of new pyrazol-4-ylpyrimidine derivatives based on our previously discovered lead compound KIST301072. Compounds 6a-e and 7a-e showed good to excellent activities against ROS1 kinase, and seven out of tested compounds were more potent than KIST301072. Compound 7c was the most potent with IC₅₀ of 24 nM. Moreover, compound 7c showed ROS1 inhibitory selectivity of about 170-fold, relative to that of ALK sharing about 49% amino acid sequence homology with ROS1 kinase in the kinase domain. In silico modeling of 7c at ROS1 active site revealed some essential features for ROS1 inhibitory activity. Based on this study as well as the previous studies, we could build a hypothetical model predicting the required essential features for ROS1 inhibitory activity. The model validity has been tested through a second set of compounds.

Original language	English
Pages (from-to)	195-208
Number of pages	14
Journal	European Journal of Medicinal Chemistry
Volume	90
DOIs	https://doi.org/10.1016/j.ejmech.2014.11.023
Publication status	Published - 2015 Jan 27

Keywords

Non-small cell lung cancer
Pyrazol-4-ylpyrimidine
ROS1 kinase inhibitor
Receptor tyrosine kinase

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

UN SDGs

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

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10.1016/j.ejmech.2014.11.023

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title = "Synthesis and biological evaluation of new pyrazol-4-ylpyrimidine derivatives as potential ROS1 kinase inhibitors",

abstract = "With the aim of discovering potent and selective kinase inhibitors targeting ROS1 kinase, we designed, synthesized and screened a series of new pyrazol-4-ylpyrimidine derivatives based on our previously discovered lead compound KIST301072. Compounds 6a-e and 7a-e showed good to excellent activities against ROS1 kinase, and seven out of tested compounds were more potent than KIST301072. Compound 7c was the most potent with IC50 of 24 nM. Moreover, compound 7c showed ROS1 inhibitory selectivity of about 170-fold, relative to that of ALK sharing about 49% amino acid sequence homology with ROS1 kinase in the kinase domain. In silico modeling of 7c at ROS1 active site revealed some essential features for ROS1 inhibitory activity. Based on this study as well as the previous studies, we could build a hypothetical model predicting the required essential features for ROS1 inhibitory activity. The model validity has been tested through a second set of compounds.",

keywords = "Non-small cell lung cancer, Pyrazol-4-ylpyrimidine, ROS1 kinase inhibitor, Receptor tyrosine kinase",

author = "Abdelazem, {Ahmed Z.} and Al-Sanea, {Mohammad M.} and Park, {Byung Sun} and Park, {Hye Mi} and Yoo, {Kyung Ho} and Taebo Sim and Park, {Jong Bae} and Lee, {Seung Hoon} and Lee, {So Ha}",

note = "Funding Information: This research was supported by Korea Institute of Science and Technology ( 2E24760 ), National Cancer Center , and a grant ( NRF-2011-0028676 ) from the creative/challenging research program of National Research Foundation of Korea . We would like to express our gratitude and thanks to Reaction Biology Corporation for carrying out the kinase screening. Publisher Copyright: {\textcopyright} 2014 Elsevier Masson SAS.",

year = "2015",

month = jan,

day = "27",

doi = "10.1016/j.ejmech.2014.11.023",

language = "English",

volume = "90",

pages = "195--208",

journal = "European Journal of Medicinal Chemistry",

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publisher = "Elsevier Masson SAS",

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TY - JOUR

T1 - Synthesis and biological evaluation of new pyrazol-4-ylpyrimidine derivatives as potential ROS1 kinase inhibitors

AU - Abdelazem, Ahmed Z.

AU - Al-Sanea, Mohammad M.

AU - Park, Byung Sun

AU - Park, Hye Mi

AU - Yoo, Kyung Ho

AU - Sim, Taebo

AU - Park, Jong Bae

AU - Lee, Seung Hoon

AU - Lee, So Ha

N1 - Funding Information: This research was supported by Korea Institute of Science and Technology ( 2E24760 ), National Cancer Center , and a grant ( NRF-2011-0028676 ) from the creative/challenging research program of National Research Foundation of Korea . We would like to express our gratitude and thanks to Reaction Biology Corporation for carrying out the kinase screening. Publisher Copyright: © 2014 Elsevier Masson SAS.

PY - 2015/1/27

Y1 - 2015/1/27

N2 - With the aim of discovering potent and selective kinase inhibitors targeting ROS1 kinase, we designed, synthesized and screened a series of new pyrazol-4-ylpyrimidine derivatives based on our previously discovered lead compound KIST301072. Compounds 6a-e and 7a-e showed good to excellent activities against ROS1 kinase, and seven out of tested compounds were more potent than KIST301072. Compound 7c was the most potent with IC50 of 24 nM. Moreover, compound 7c showed ROS1 inhibitory selectivity of about 170-fold, relative to that of ALK sharing about 49% amino acid sequence homology with ROS1 kinase in the kinase domain. In silico modeling of 7c at ROS1 active site revealed some essential features for ROS1 inhibitory activity. Based on this study as well as the previous studies, we could build a hypothetical model predicting the required essential features for ROS1 inhibitory activity. The model validity has been tested through a second set of compounds.

AB - With the aim of discovering potent and selective kinase inhibitors targeting ROS1 kinase, we designed, synthesized and screened a series of new pyrazol-4-ylpyrimidine derivatives based on our previously discovered lead compound KIST301072. Compounds 6a-e and 7a-e showed good to excellent activities against ROS1 kinase, and seven out of tested compounds were more potent than KIST301072. Compound 7c was the most potent with IC50 of 24 nM. Moreover, compound 7c showed ROS1 inhibitory selectivity of about 170-fold, relative to that of ALK sharing about 49% amino acid sequence homology with ROS1 kinase in the kinase domain. In silico modeling of 7c at ROS1 active site revealed some essential features for ROS1 inhibitory activity. Based on this study as well as the previous studies, we could build a hypothetical model predicting the required essential features for ROS1 inhibitory activity. The model validity has been tested through a second set of compounds.

KW - Non-small cell lung cancer

KW - Pyrazol-4-ylpyrimidine

KW - ROS1 kinase inhibitor

KW - Receptor tyrosine kinase

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ER -

Synthesis and biological evaluation of new pyrazol-4-ylpyrimidine derivatives as potential ROS1 kinase inhibitors

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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