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

Title
Small molecule activator of Nm23/NDPK as an inhibitor of metastasis
Authors
김은경신상철Jae-Jin LeeHwang Suk KimJimin ParkSoonwha SongEunsun LeeJung-Eun ChoiJi-Wan SuhHongsoo LeeEun Kyoung SeoDong Hae ShinHo-Young LeeHee-Yoon LeeKong-Joo LeeJi-Sun Lee
Issue Date
2018-07
Publisher
Scientific Reports
Citation
VOL 19, NO 8-10909-13
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.
URI
http://pubs.kist.re.kr/handle/201004/68052
ISSN
2045-2322
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KIST Publication > Article
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