2. Academic Validation
  3. Small molecule activator of Nm23/NDPK as an inhibitor of metastasis

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

  • Sci Rep. 2018 Jul 19;8(1):10909. doi: 10.1038/s41598-018-29101-6.
Jae-Jin Lee 1,  Hwang Suk Kim 2,  Ji-Sun Lee 3,  Jimin Park 1,  Sang Chul Shin 4,  Soonwha Song 1,  Eunsun Lee 1,  Jung-Eun Choi 1,  Ji-Wan Suh 1,  Hongsoo Lee 2,  Eunice EunKyeong Kim 4,  Eun Kyoung Seo 1,  Dong Hae Shin 1,  Ho-Young Lee 3,  Hee-Yoon Lee 5,  Kong-Joo Lee 6
Affiliations

Affiliations

  • 1 Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, 03760, Korea.
  • 2 Department of Chemistry, Korea Advanced Institute of Science & Technology, Daejeon, 34141, Korea.
  • 3 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Korea.
  • 4 Biomedical Research Institute, Korea Institute of Science & Technology, Seoul, 02792, Korea.
  • 5 Department of Chemistry, Korea Advanced Institute of Science & Technology, Daejeon, 34141, Korea. leehy@kaist.ac.kr.
  • 6 Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, 03760, Korea. kjl@ewha.ac.kr.
PMID: 30026594 DOI: 10.1038/s41598-018-29101-6
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.

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