Small molecule activator of Nm23/NDPK as an inhibitor of metastasis

Jae Jin Lee; Hwang Suk Kim; Ji Sun Lee; Jimin Park; Sang Chul Shin; Soonwha Song; Eunsun Lee; Jung Eun Choi; Ji Wan Suh; Hongsoo Lee; Eunice Eun Kyeong Kim; Eun Kyoung Seo; Dong Hae Shin; Ho Young Lee; Hee Yoon Lee; Kong Joo Lee

doi:10.1038/s41598-018-29101-6

Small molecule activator of Nm23/NDPK as an inhibitor of metastasis

Jae Jin Lee, Hwang Suk Kim, Ji Sun Lee, Jimin Park, Sang Chul Shin, Soonwha Song, Eunsun Lee, Jung Eun Choi, Ji Wan Suh, Hongsoo Lee, Eunice Eun Kyeong Kim, Eun Kyoung Seo, Dong Hae Shin, Ho Young Lee, Hee Yoon Lee, Kong Joo Lee

Department of Pharmaceutical Sciences

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

18 Scopus citations

Abstract

Nm23-H1/NDPK-A is a tumor metastasis suppressor having NDP kinase (NDPK) activity. Nm23-H1 is positively associated with prolonged disease-free survival and good prognosis of cancer patients. Approaches to increasing the cellular levels of Nm23-H1 therefore have significance in the therapy of metastatic cancers. We found a small molecule, (±)-trans-3-(3,4-dimethoxyphenyl)-4-[(E)-3,4-dimethoxystyryl]cyclohex-1-ene, that activates Nm23, hereafter called NMac1. NMac1 directly binds to Nm23-H1 and increases its NDPK activity. Employing various NMac1 derivatives and hydrogen/deuterium mass spectrometry (HDX-MS), we identified the pharmacophore and mode of action of NMac1. We found that NMac1 binds to the C-terminal of Nm23-H1 and induces the NDPK activation through its allosteric conformational changes. NMac1-treated MDA-MB-231 breast cancer cells showed dramatic changes in morphology and actin-cytoskeletal organization following inhibition of Rac1 activation. NMac1 also suppressed invasion and migration in vitro, and metastasis in vivo, in a breast cancer mouse model. NMac1 as an activator of NDPK has potential as an anti-metastatic agent.

Original language	English
Article number	10909
Journal	Scientific Reports
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41598-018-29101-6
State	Published - 1 Dec 2018

Bibliographical note

Funding Information:
This work was supported by the Global Research Lab Program (No. 2012K1A1A2045441), and Research Fellowship (No. 2015R1D1A4A01019646) of National Research Foundation of Korea. SS, JEC and JWS were supported by Brain Korea 21 Plus (BK21 Plus) Project.

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© 2018, The Author(s).

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@article{2358e086ea244437976319ef912261a6,

title = "Small molecule activator of Nm23/NDPK as an inhibitor of metastasis",

abstract = "Nm23-H1/NDPK-A is a tumor metastasis suppressor having NDP kinase (NDPK) activity. Nm23-H1 is positively associated with prolonged disease-free survival and good prognosis of cancer patients. Approaches to increasing the cellular levels of Nm23-H1 therefore have significance in the therapy of metastatic cancers. We found a small molecule, (±)-trans-3-(3,4-dimethoxyphenyl)-4-[(E)-3,4-dimethoxystyryl]cyclohex-1-ene, that activates Nm23, hereafter called NMac1. NMac1 directly binds to Nm23-H1 and increases its NDPK activity. Employing various NMac1 derivatives and hydrogen/deuterium mass spectrometry (HDX-MS), we identified the pharmacophore and mode of action of NMac1. We found that NMac1 binds to the C-terminal of Nm23-H1 and induces the NDPK activation through its allosteric conformational changes. NMac1-treated MDA-MB-231 breast cancer cells showed dramatic changes in morphology and actin-cytoskeletal organization following inhibition of Rac1 activation. NMac1 also suppressed invasion and migration in vitro, and metastasis in vivo, in a breast cancer mouse model. NMac1 as an activator of NDPK has potential as an anti-metastatic agent.",

author = "Lee, {Jae Jin} and Kim, {Hwang Suk} and Lee, {Ji Sun} and Jimin Park and Shin, {Sang Chul} and Soonwha Song and Eunsun Lee and Choi, {Jung Eun} and Suh, {Ji Wan} and Hongsoo Lee and Kim, {Eunice Eun Kyeong} and Seo, {Eun Kyoung} and Shin, {Dong Hae} and Lee, {Ho Young} and Lee, {Hee Yoon} and Lee, {Kong Joo}",

note = "Funding Information: This work was supported by the Global Research Lab Program (No. 2012K1A1A2045441), and Research Fellowship (No. 2015R1D1A4A01019646) of National Research Foundation of Korea. SS, JEC and JWS were supported by Brain Korea 21 Plus (BK21 Plus) Project. Publisher Copyright: {\textcopyright} 2018, The Author(s).",

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doi = "10.1038/s41598-018-29101-6",

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T1 - Small molecule activator of Nm23/NDPK as an inhibitor of metastasis

AU - Lee, Jae Jin

AU - Kim, Hwang Suk

AU - Lee, Ji Sun

AU - Park, Jimin

AU - Shin, Sang Chul

AU - Song, Soonwha

AU - Lee, Eunsun

AU - Choi, Jung Eun

AU - Suh, Ji Wan

AU - Lee, Hongsoo

AU - Kim, Eunice Eun Kyeong

AU - Seo, Eun Kyoung

AU - Shin, Dong Hae

AU - Lee, Ho Young

AU - Lee, Hee Yoon

AU - Lee, Kong Joo

N1 - Funding Information: This work was supported by the Global Research Lab Program (No. 2012K1A1A2045441), and Research Fellowship (No. 2015R1D1A4A01019646) of National Research Foundation of Korea. SS, JEC and JWS were supported by Brain Korea 21 Plus (BK21 Plus) Project. Publisher Copyright: © 2018, The Author(s).

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Nm23-H1/NDPK-A is a tumor metastasis suppressor having NDP kinase (NDPK) activity. Nm23-H1 is positively associated with prolonged disease-free survival and good prognosis of cancer patients. Approaches to increasing the cellular levels of Nm23-H1 therefore have significance in the therapy of metastatic cancers. We found a small molecule, (±)-trans-3-(3,4-dimethoxyphenyl)-4-[(E)-3,4-dimethoxystyryl]cyclohex-1-ene, that activates Nm23, hereafter called NMac1. NMac1 directly binds to Nm23-H1 and increases its NDPK activity. Employing various NMac1 derivatives and hydrogen/deuterium mass spectrometry (HDX-MS), we identified the pharmacophore and mode of action of NMac1. We found that NMac1 binds to the C-terminal of Nm23-H1 and induces the NDPK activation through its allosteric conformational changes. NMac1-treated MDA-MB-231 breast cancer cells showed dramatic changes in morphology and actin-cytoskeletal organization following inhibition of Rac1 activation. NMac1 also suppressed invasion and migration in vitro, and metastasis in vivo, in a breast cancer mouse model. NMac1 as an activator of NDPK has potential as an anti-metastatic agent.

AB - Nm23-H1/NDPK-A is a tumor metastasis suppressor having NDP kinase (NDPK) activity. Nm23-H1 is positively associated with prolonged disease-free survival and good prognosis of cancer patients. Approaches to increasing the cellular levels of Nm23-H1 therefore have significance in the therapy of metastatic cancers. We found a small molecule, (±)-trans-3-(3,4-dimethoxyphenyl)-4-[(E)-3,4-dimethoxystyryl]cyclohex-1-ene, that activates Nm23, hereafter called NMac1. NMac1 directly binds to Nm23-H1 and increases its NDPK activity. Employing various NMac1 derivatives and hydrogen/deuterium mass spectrometry (HDX-MS), we identified the pharmacophore and mode of action of NMac1. We found that NMac1 binds to the C-terminal of Nm23-H1 and induces the NDPK activation through its allosteric conformational changes. NMac1-treated MDA-MB-231 breast cancer cells showed dramatic changes in morphology and actin-cytoskeletal organization following inhibition of Rac1 activation. NMac1 also suppressed invasion and migration in vitro, and metastasis in vivo, in a breast cancer mouse model. NMac1 as an activator of NDPK has potential as an anti-metastatic agent.

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U2 - 10.1038/s41598-018-29101-6

DO - 10.1038/s41598-018-29101-6

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AN - SCOPUS:85050625065

SN - 2045-2322

VL - 8

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 10909

ER -

Small molecule activator of Nm23/NDPK as an inhibitor of metastasis

Abstract

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