Lee, Jae-Jin Kim, Hwang Suk Lee, Ji-Sun Park, Jimin Shin, Sang Chul Song, Soonwha Lee, Eunsun Choi, Jung-Eun Suh, Ji-Wan Lee, Hongsoo Kim, Eunice EunKyeong Seo, Eun Kyoung Shin, Dong Hae Lee, Ho-Young Lee, Hee-Yoon Lee, Kong-Joo 2024-01-19T22:04:48Z 2024-01-19T22:04:48Z 2021-09-03 2018-07-19 2045-2322 https://pubs.kist.re.kr/handle/201004/121144 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. English NATURE PUBLISHING GROUP NUCLEOSIDE DIPHOSPHATE KINASE ZINGIBER-CASSUMUNAR ROXB LYMPH-NODE METASTASIS MEDROXYPROGESTERONE ACETATE BREAST-CANCER ALLOSTERIC ACTIVATORS PHENYLBUTENOID DIMER ADHERENS JUNCTIONS MASS-SPECTROMETRY TUMOR-METASTASIS Small molecule activator of Nm23/NDPK as an inhibitor of metastasis Article 10.1038/s41598-018-29101-6 1 SCIENTIFIC REPORTS, v.8 SCIENTIFIC REPORTS 8 scie scopus 000439101600008 2-s2.0-85050625065 Multidisciplinary Sciences Science & Technology - Other Topics Article NUCLEOSIDE DIPHOSPHATE KINASE ZINGIBER-CASSUMUNAR ROXB LYMPH-NODE METASTASIS MEDROXYPROGESTERONE ACETATE BREAST-CANCER ALLOSTERIC ACTIVATORS PHENYLBUTENOID DIMER ADHERENS JUNCTIONS MASS-SPECTROMETRY TUMOR-METASTASIS