Pyrazolo[1,5-a]pyrimidine TRPC6 antagonists for the treatment of gastric cancer

Mingmin Ding; Hongbo Wang; Chunrong Qu; Fuchun Xu; Yingmin Zhu; Guangyao Lv; Yungang Lu; Qingjun Zhou; Hui Zhou; Xiaodong Zeng; Jingwen Zhang; Chunhong Yan; Jiacheng Lin; Huai Rong Luo; Zixing Deng; Yuling Xiao; Jinbin Tian; Michael X. Zhu; Xuechuan Hong

doi:10.1016/j.canlet.2018.05.041

Pyrazolo[1,5-a]pyrimidine TRPC6 antagonists for the treatment of gastric cancer

Mingmin Ding, Hongbo Wang, Chunrong Qu, Fuchun Xu, Yingmin Zhu, Guangyao Lv, Yungang Lu, Qingjun Zhou, Hui Zhou, Xiaodong Zeng, Jingwen Zhang, Chunhong Yan, Jiacheng Lin, Huai Rong Luo, Zixing Deng, Yuling Xiao, Jinbin Tian, Michael X. Zhu, Xuechuan Hong

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

43 Scopus citations

Abstract

Transient receptor potential canonical 6 (TRPC6) proteins form receptor-operated Ca²⁺-permeable channels, which have been thought to bring benefit to the treatment of diseases, including cancer. However, selective antagonists for TRPC channels are rare and none of them has been tested against gastric cancer. Compound 14a and analogs were synthesized by chemical elaboration of previously reported TRPC3/6/7 agonist 4o. 14a had very weak agonist activity at TRPC6 expressed in HEK293 cells but exhibited strong inhibition on both 4o-mediated and receptor-operated activation of TRPC6 with an IC₅₀ of about 1 μM. When applied to the culture media, 14a suppressed proliferation of AGS and MKN45 cells with IC₅₀ values of 17.1 ± 0.3 and 18.5 ± 1.0 μM, respectively, and inhibited tube formation and migration of cultured human endothelial cells. This anti-tumor effect on gastric cancer was further verified in xenograft models using nude mice. This study has found a new tool compound which shows excellent therapeutic potential against human gastric cancer most likely through targeting TRPC6 channels.

Original language	English (US)
Pages (from-to)	47-55
Number of pages	9
Journal	Cancer Letters
Volume	432
DOIs	https://doi.org/10.1016/j.canlet.2018.05.041
State	Published - Sep 28 2018
Externally published	Yes

Keywords

Anticancer
Ca signaling
Drug discovery
Nonselective cation channels
TRPC channels

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

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

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10.1016/j.canlet.2018.05.041

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title = "Pyrazolo[1,5-a]pyrimidine TRPC6 antagonists for the treatment of gastric cancer",

abstract = "Transient receptor potential canonical 6 (TRPC6) proteins form receptor-operated Ca2+-permeable channels, which have been thought to bring benefit to the treatment of diseases, including cancer. However, selective antagonists for TRPC channels are rare and none of them has been tested against gastric cancer. Compound 14a and analogs were synthesized by chemical elaboration of previously reported TRPC3/6/7 agonist 4o. 14a had very weak agonist activity at TRPC6 expressed in HEK293 cells but exhibited strong inhibition on both 4o-mediated and receptor-operated activation of TRPC6 with an IC50 of about 1 μM. When applied to the culture media, 14a suppressed proliferation of AGS and MKN45 cells with IC50 values of 17.1 ± 0.3 and 18.5 ± 1.0 μM, respectively, and inhibited tube formation and migration of cultured human endothelial cells. This anti-tumor effect on gastric cancer was further verified in xenograft models using nude mice. This study has found a new tool compound which shows excellent therapeutic potential against human gastric cancer most likely through targeting TRPC6 channels.",

keywords = "Anticancer, Ca signaling, Drug discovery, Nonselective cation channels, TRPC channels",

author = "Mingmin Ding and Hongbo Wang and Chunrong Qu and Fuchun Xu and Yingmin Zhu and Guangyao Lv and Yungang Lu and Qingjun Zhou and Hui Zhou and Xiaodong Zeng and Jingwen Zhang and Chunhong Yan and Jiacheng Lin and Luo, {Huai Rong} and Zixing Deng and Yuling Xiao and Jinbin Tian and Zhu, {Michael X.} and Xuechuan Hong",

note = "Publisher Copyright: {\textcopyright} 2018 Elsevier B.V.",

year = "2018",

month = sep,

day = "28",

doi = "10.1016/j.canlet.2018.05.041",

language = "English (US)",

volume = "432",

pages = "47--55",

journal = "Cancer Letters",

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TY - JOUR

T1 - Pyrazolo[1,5-a]pyrimidine TRPC6 antagonists for the treatment of gastric cancer

AU - Ding, Mingmin

AU - Wang, Hongbo

AU - Qu, Chunrong

AU - Xu, Fuchun

AU - Zhu, Yingmin

AU - Lv, Guangyao

AU - Lu, Yungang

AU - Zhou, Qingjun

AU - Zhou, Hui

AU - Zeng, Xiaodong

AU - Zhang, Jingwen

AU - Yan, Chunhong

AU - Lin, Jiacheng

AU - Luo, Huai Rong

AU - Deng, Zixing

AU - Xiao, Yuling

AU - Tian, Jinbin

AU - Zhu, Michael X.

AU - Hong, Xuechuan

PY - 2018/9/28

Y1 - 2018/9/28

N2 - Transient receptor potential canonical 6 (TRPC6) proteins form receptor-operated Ca2+-permeable channels, which have been thought to bring benefit to the treatment of diseases, including cancer. However, selective antagonists for TRPC channels are rare and none of them has been tested against gastric cancer. Compound 14a and analogs were synthesized by chemical elaboration of previously reported TRPC3/6/7 agonist 4o. 14a had very weak agonist activity at TRPC6 expressed in HEK293 cells but exhibited strong inhibition on both 4o-mediated and receptor-operated activation of TRPC6 with an IC50 of about 1 μM. When applied to the culture media, 14a suppressed proliferation of AGS and MKN45 cells with IC50 values of 17.1 ± 0.3 and 18.5 ± 1.0 μM, respectively, and inhibited tube formation and migration of cultured human endothelial cells. This anti-tumor effect on gastric cancer was further verified in xenograft models using nude mice. This study has found a new tool compound which shows excellent therapeutic potential against human gastric cancer most likely through targeting TRPC6 channels.

AB - Transient receptor potential canonical 6 (TRPC6) proteins form receptor-operated Ca2+-permeable channels, which have been thought to bring benefit to the treatment of diseases, including cancer. However, selective antagonists for TRPC channels are rare and none of them has been tested against gastric cancer. Compound 14a and analogs were synthesized by chemical elaboration of previously reported TRPC3/6/7 agonist 4o. 14a had very weak agonist activity at TRPC6 expressed in HEK293 cells but exhibited strong inhibition on both 4o-mediated and receptor-operated activation of TRPC6 with an IC50 of about 1 μM. When applied to the culture media, 14a suppressed proliferation of AGS and MKN45 cells with IC50 values of 17.1 ± 0.3 and 18.5 ± 1.0 μM, respectively, and inhibited tube formation and migration of cultured human endothelial cells. This anti-tumor effect on gastric cancer was further verified in xenograft models using nude mice. This study has found a new tool compound which shows excellent therapeutic potential against human gastric cancer most likely through targeting TRPC6 channels.

KW - Anticancer

KW - Ca signaling

KW - Drug discovery

KW - Nonselective cation channels

KW - TRPC channels

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JO - Cancer Letters

JF - Cancer Letters

ER -

Pyrazolo[1,5-a]pyrimidine TRPC6 antagonists for the treatment of gastric cancer

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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