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Selective Small-Molecule Targeting of a Triple Helix Encoded by the Long Noncoding RNA, MALAT1

Fardokht A Abulwerdi1, Wenbo Xu2,3, Abeer A Ageeli4

  • 1Basic Research Laboratory, Center for Cancer Research , National Cancer Institute , Frederick , Maryland 21702 , United States.

ACS Chemical Biology
|January 9, 2019
PubMed

Insights

Researchers identified small molecules that target the Malat1 long noncoding RNA

Area of Science:

  • Molecular Biology
  • Genomics
  • Cancer Research

Background:

  • Metastasis-associated lung adenocarcinoma transcript 1 (Malat1) is a long noncoding RNA implicated in cancer progression.
  • The Malat1 3' terminal stability element for nuclear expression (ENE) is crucial for its nuclear localization and function.
  • Targeting Malat1 offers a potential therapeutic strategy for various cancers.

Purpose of the Study:

  • To identify small molecules that bind to the Malat1 ENE triplex.
  • To investigate the effects of these molecules on Malat1 RNA levels and cancer cell behavior.
  • To explore the specificity of these compounds for Malat1.

Main Methods:

  • Small molecule microarray screening to identify ENE-binding compounds.
  • Mammary tumor organoid models to assess effects on branching morphogenesis.
  • Computational modeling, FRET, and NMR spectroscopy to determine binding modes and specificity.

Main Results:

  • Multiple chemotypes targeting the Malat1 ENE triplex were identified.
  • Compounds 5 and 16 reduced Malat1 RNA levels and affected tumor organoid development.
  • Compound 5 demonstrated specificity for Malat1 over Neat1 and viral ENEs, with distinct binding mechanisms.

Conclusions:

  • Small molecules targeting the Malat1 ENE triplex can modulate Malat1 function.
  • These compounds represent potential therapeutic agents for Malat1-driven cancers.
  • Specific targeting of Malat1 ENE provides a foundation for novel anticancer drugs and research tools.

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