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

Scientific Reports
Jae-Jin LeeKong-Joo Lee

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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Citations

Aug 23, 2020·International Journal of Molecular Sciences·Kevin AdamTony Hunter
Jan 10, 2021·Life Sciences·Liting YuChangying Guo
Mar 24, 2021·Experimental & Molecular Medicine·Bokyung Kim, Kong-Joo Lee
May 1, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Ah-Reum HanEun Kyoung Seo

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Methods Mentioned

BETA
size exclusion chromatography
surface plasmon resonance
GTPase
confocal microscopy
pulldown
chip

Software Mentioned

Kaleida Graph
DynamX
- Dock
SYBYL sketcher
Scrubber
Excel
Tripos
SYBYL
Origin
Surflex

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