Design and Optimization of 3′-(Imidazo[1,2-a]pyrazin-3-yl)-[1,1′-biphenyl]-3-carboxamides as Selective DDR1 Inhibitors

Cheng Mo; Zhang Zhang; Yupeng Li; Minhao Huang; Jian Zou; Jinfeng Luo; Zheng-Chao Tu; Yong Xu; Xiaomei Ren; Ke Ding; Xiaoyun Lu

doi:10.1021/acsmedchemlett.9b00495

Design and Optimization of 3′-(Imidazo[1,2-a]pyrazin-3-yl)-[1,1′-biphenyl]-3-carboxamides as Selective DDR1 Inhibitors

Cheng Mo
, Zhang Zhang
, Yupeng Li
, Minhao Huang
, Jian Zou
, Jinfeng Luo
, Zheng-Chao Tu
, Yong Xu
, Xiaomei Ren
, Ke Ding
, Xiaoyun Lu

Carcinogenesis and Chemoprevention

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

19 Scopus citations

Abstract

DDR1 is considered as a promising target for cancer therapy, and selective inhibitors against DDR1 over other kinases may be considered as promising therapeutic agents. Herein, we have identified a series of 3′-(imidazo[1,2-a]pyrazin-3-yl)-[1,1′-biphenyl]-3-carboxamides as novel selective DDR1 inhibitors. Among these, compound 8v potently inhibited DDR1 with an IC ₅₀ of 23.8 nM, while it showed less inhibitory activity against DDR2 (IC ₅₀ = 1740 nM) and negligible activities against Bcr-Abl (IC ₅₀ > 10 μM) and c-Kit (IC ₅₀ > 10 μM). 8v also exhibited excellent selectivity in a KINOMEscan screening platform with 468 kinases. This compound dose-dependently suppressed NSCLC cell tumorigenicity, migration, and invasion. Collectively, these studies support its potential application for treatment of NSCLC.

Original language	English
Pages (from-to)	379-384
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	11
Issue number	3
DOIs	https://doi.org/10.1021/acsmedchemlett.9b00495
State	Published - Mar 12 2020

Bibliographical note

Funding Information:
This work was supported by National Natural Science Foundation of China (81922062, 81874285, and 81820108029), National Key Research and Development Program of China (218YFE0105800), and Guangdong Province Science and Technology Program (2018A050506043) and Jinan University.

Publisher Copyright:
Copyright © 2020 American Chemical Society.

UN SDGs

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

SDG 3 Good Health and Well-being

Keywords

DDR1
NSCLC
SAR
drug discovery
selective inhibitor

PubMed: MeSH publication types

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10.1021/acsmedchemlett.9b00495

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title = "Design and Optimization of 3′-(Imidazo[1,2-a]pyrazin-3-yl)-[1,1′-biphenyl]-3-carboxamides as Selective DDR1 Inhibitors",

abstract = "DDR1 is considered as a promising target for cancer therapy, and selective inhibitors against DDR1 over other kinases may be considered as promising therapeutic agents. Herein, we have identified a series of 3′-(imidazo[1,2-a]pyrazin-3-yl)-[1,1′-biphenyl]-3-carboxamides as novel selective DDR1 inhibitors. Among these, compound 8v potently inhibited DDR1 with an IC 50 of 23.8 nM, while it showed less inhibitory activity against DDR2 (IC 50 = 1740 nM) and negligible activities against Bcr-Abl (IC 50 > 10 μM) and c-Kit (IC 50 > 10 μM). 8v also exhibited excellent selectivity in a KINOMEscan screening platform with 468 kinases. This compound dose-dependently suppressed NSCLC cell tumorigenicity, migration, and invasion. Collectively, these studies support its potential application for treatment of NSCLC. ",

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note = "Funding Information: This work was supported by National Natural Science Foundation of China (81922062, 81874285, and 81820108029), National Key Research and Development Program of China (218YFE0105800), and Guangdong Province Science and Technology Program (2018A050506043) and Jinan University. Publisher Copyright: Copyright {\textcopyright} 2020 American Chemical Society.",

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doi = "10.1021/acsmedchemlett.9b00495",

language = "English",

volume = "11",

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AU - Mo, Cheng

AU - Zhang, Zhang

AU - Li, Yupeng

AU - Huang, Minhao

AU - Zou, Jian

AU - Luo, Jinfeng

AU - Tu, Zheng-Chao

AU - Xu, Yong

AU - Ren, Xiaomei

AU - Ding, Ke

AU - Lu, Xiaoyun

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PY - 2020/3/12

Y1 - 2020/3/12

N2 - DDR1 is considered as a promising target for cancer therapy, and selective inhibitors against DDR1 over other kinases may be considered as promising therapeutic agents. Herein, we have identified a series of 3′-(imidazo[1,2-a]pyrazin-3-yl)-[1,1′-biphenyl]-3-carboxamides as novel selective DDR1 inhibitors. Among these, compound 8v potently inhibited DDR1 with an IC 50 of 23.8 nM, while it showed less inhibitory activity against DDR2 (IC 50 = 1740 nM) and negligible activities against Bcr-Abl (IC 50 > 10 μM) and c-Kit (IC 50 > 10 μM). 8v also exhibited excellent selectivity in a KINOMEscan screening platform with 468 kinases. This compound dose-dependently suppressed NSCLC cell tumorigenicity, migration, and invasion. Collectively, these studies support its potential application for treatment of NSCLC.

AB - DDR1 is considered as a promising target for cancer therapy, and selective inhibitors against DDR1 over other kinases may be considered as promising therapeutic agents. Herein, we have identified a series of 3′-(imidazo[1,2-a]pyrazin-3-yl)-[1,1′-biphenyl]-3-carboxamides as novel selective DDR1 inhibitors. Among these, compound 8v potently inhibited DDR1 with an IC 50 of 23.8 nM, while it showed less inhibitory activity against DDR2 (IC 50 = 1740 nM) and negligible activities against Bcr-Abl (IC 50 > 10 μM) and c-Kit (IC 50 > 10 μM). 8v also exhibited excellent selectivity in a KINOMEscan screening platform with 468 kinases. This compound dose-dependently suppressed NSCLC cell tumorigenicity, migration, and invasion. Collectively, these studies support its potential application for treatment of NSCLC.

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Design and Optimization of 3′-(Imidazo[1,2-a]pyrazin-3-yl)-[1,1′-biphenyl]-3-carboxamides as Selective DDR1 Inhibitors

Abstract

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