Unknown

Dataset Information

0

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


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.

SUBMITTER: Lee JJ 

PROVIDER: S-EPMC6053448 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

altmetric image

Publications


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 i  ...[more]

Similar Datasets

| S-EPMC7461546 | biostudies-literature
2020-05-30 | GSE151491 | GEO
| S-EPMC4514594 | biostudies-literature
| S-EPMC6315020 | biostudies-literature
| S-EPMC4946882 | biostudies-other
| S-EPMC3870673 | biostudies-literature
| S-EPMC3543036 | biostudies-literature
| S-EPMC7510951 | biostudies-literature
2020-05-17 | MSV000085432 | MassIVE
| S-EPMC4538829 | biostudies-literature