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Updated: May 31, 2025
High-throughput Screening for Chemical Modulators of Post-transcriptionally Regulated Genes
Published on: March 3, 2015
A comprehensive high-throughput screening approach for discovering inhibitors targeting the menin-MLL1 interaction
Tamizhini Loganathan1, George Priya Doss C1
1Laboratory of Integrative Genomics, Department of Integrative Biology, School of BioSciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India.
Abstract:
The prognosis for mixed-lineage leukemia (MLL), particularly in young children, remains a significant health concern due to the limited therapeutic options available. MLL refers to KMT2A chromosomal translocations that produce MLL fusion proteins. The protein menin, which is essential for the malignant potential of these MLL fusion proteins, offers novel targets for acute leukemia treatment. This study reports the identification of potential new inhibitors of MLL-mediated leukemia targeting menin through the screening of two distinct drug libraries and existing inhibitors. The 3D structure of the protein was retrieved from the Protein Data Bank (ID: 8IG0). The drug libraries, sourced from public repositories such as the 'Epigenetic Drug Library' and 'The FDA-anticancer Drug Library,' yielded top candidates like Tozaseritib and Panobinostat, which exhibited the highest binding energy scores in the Glide virtual screening module. Additionally, 31 known menin-MLL1 inhibitors were identified through PDB screening and subsequently docked with the menin protein. The top three inhibitors (M-525, M-808, and MI-89) were selected for further analysis. Five menin-ligand complexes were validated using molecular dynamics analysis and Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations to verify the stability and binding mechanisms.These findings provide insights into the molecular mechanisms of these drugs and lay the groundwork for future clinical development aimed at improving outcomes for acute myeloid leukemia (AML) patients.
Insights
Researchers identified new potential drugs targeting menin for treating mixed-lineage leukemia (MLL). This discovery offers hope for better therapeutic options for acute myeloid leukemia (AML) patients.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Mixed-lineage leukemia (MLL), driven by KMT2A translocations, presents a poor prognosis, especially in pediatric cases, due to limited treatment strategies.
- The menin protein is crucial for the oncogenic activity of MLL fusion proteins, making it a promising therapeutic target.
- Developing novel menin inhibitors is essential for advancing acute myeloid leukemia (AML) treatment.
Purpose of the Study:
- To identify and evaluate novel inhibitors of the menin protein for the treatment of MLL-mediated leukemia.
- To screen existing drug libraries and known menin inhibitors for potential therapeutic candidates.
- To validate the binding stability and mechanisms of identified menin inhibitors.
Main Methods:
- Virtual screening of the Epigenetic Drug Library and FDA-anticancer Drug Library using the Glide module.
- Retrieval of the menin protein 3D structure (PDB ID: 8IG0) for docking studies.
- Identification and docking of 31 known menin-MLL1 inhibitors.
- Molecular dynamics analysis and MM-PBSA calculations for complex validation.
Main Results:
- Tozaseritib and Panobinostat emerged as top candidates from library screening, showing high binding energy scores.
- M-525, M-808, and MI-89 were identified as the most promising known menin-MLL1 inhibitors after docking.
- Molecular dynamics and MM-PBSA confirmed the stability and binding mechanisms of five menin-ligand complexes.
Conclusions:
- This study successfully identified potential novel menin inhibitors for MLL-mediated leukemia.
- The findings provide valuable insights into drug-protein interactions and mechanisms.
- The validated inhibitors represent promising candidates for further preclinical and clinical development in AML treatment.
