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

Authors
Lee, Jae-JinKim, Hwang SukLee, Ji-SunPark, JiminShin, Sang ChulSong, SoonwhaLee, EunsunChoi, Jung-EunSuh, Ji-WanLee, HongsooKim, Eunice EunKyeongSeo, Eun KyoungShin, Dong HaeLee, Ho-YoungLee, Hee-YoonLee, Kong-Joo
Issue Date
2018-07-19
Publisher
NATURE PUBLISHING GROUP
Citation
SCIENTIFIC REPORTS, v.8
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.
Keywords
NUCLEOSIDE DIPHOSPHATE KINASE; ZINGIBER-CASSUMUNAR ROXB; LYMPH-NODE METASTASIS; MEDROXYPROGESTERONE ACETATE; BREAST-CANCER; ALLOSTERIC ACTIVATORS; PHENYLBUTENOID DIMER; ADHERENS JUNCTIONS; MASS-SPECTROMETRY; TUMOR-METASTASIS; NUCLEOSIDE DIPHOSPHATE KINASE; ZINGIBER-CASSUMUNAR ROXB; LYMPH-NODE METASTASIS; MEDROXYPROGESTERONE ACETATE; BREAST-CANCER; ALLOSTERIC ACTIVATORS; PHENYLBUTENOID DIMER; ADHERENS JUNCTIONS; MASS-SPECTROMETRY; TUMOR-METASTASIS
ISSN
2045-2322
URI
https://pubs.kist.re.kr/handle/201004/121144
DOI
10.1038/s41598-018-29101-6
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KIST Article > 2018
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