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
  • 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. [email protected].
  • 6. Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, 03760, Korea. [email protected].
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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