Hit identification of novel small molecules interfering with MALAT1 triplex by a structure-based virtual screening
Roberta Rocca1,2, Nicoletta Polerà1, Giada Juli1
1Department of Experimental and Clinical Medicine, Università degli Studi "Magna Graecia" di Catanzaro, Campus "Salvatore Venuta", Catanzaro, Italy.
Researchers identified a novel small molecule, M5, that destabilizes the MALAT1 RNA structure. This compound shows antiproliferative activity against multiple myeloma, offering a promising lead for new cancer therapies.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Long noncoding RNAs (lncRNAs) are implicated in cancer development.
- Overexpression of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is linked to multiple myeloma (MM) pathogenesis.
Purpose of the Study:
- To identify small molecules targeting the MALAT1 RNA structure for potential therapeutic intervention in multiple myeloma.
Main Methods:
- Structure-based virtual screening of a drug-like compound database using the MALAT1 triple-helical stability element structure.
- Thermodynamic analysis to filter compounds.
- In vitro assays to evaluate compound efficacy.
Main Results:
- A diazaindene-based compound, M5, was identified as the most promising molecule.
- M5 effectively destabilized the MALAT1 triplex structure.
- M5 demonstrated antiproliferative activity in in vitro multiple myeloma models.
Conclusions:
- M5 is a potent lead compound for developing novel therapeutics targeting MALAT1 in multiple myeloma.
- Further optimization of M5 is warranted to enhance its affinity and therapeutic potential.
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