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

Jae-Jin Lee1, Hwang Suk Kim2, Ji-Sun Lee3

  • 1Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, 03760, Korea.

Scientific Reports
|July 21, 2018
PubMed

Insights

A novel small molecule, NMac1, activates Nm23-H1 (nucleoside diphosphate kinase A), a tumor metastasis suppressor. This activation inhibits cancer cell invasion and migration, showing potential as an anti-metastatic therapy.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Nm23-H1/NDPK-A is a key tumor metastasis suppressor.
  • Increased Nm23-H1 levels correlate with better cancer patient prognosis.
  • Targeting Nm23-H1 is a promising strategy for anti-metastatic cancer therapies.

Purpose of the Study:

  • To identify and characterize small molecules that enhance Nm23-H1 activity.
  • To elucidate the mechanism of action for NMac1, a novel Nm23-H1 activator.
  • To evaluate the anti-metastatic potential of NMac1 in preclinical models.

Main Methods:

  • Small molecule screening and synthesis of NMac1 derivatives.
  • Hydrogen/deuterium mass spectrometry (HDX-MS) for pharmacophore identification.
  • In vitro cell-based assays (morphology, invasion, migration) and in vivo metastasis mouse model.

Main Results:

  • NMac1 directly binds to Nm23-H1, increasing its NDPK activity via allosteric conformational changes.
  • NMac1 treatment altered cancer cell morphology and actin cytoskeleton, inhibiting Rac1 activation.
  • NMac1 suppressed breast cancer cell invasion and migration in vitro and metastasis in vivo.

Conclusions:

  • NMac1 is a potent activator of Nm23-H1 with demonstrated anti-metastatic properties.
  • The findings support NMac1's potential as a therapeutic agent for metastatic cancers.
  • Understanding NMac1's mechanism provides insights into Nm23-H1 function in metastasis.

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