qHTS Assay for Inhibitors Targeting the Menin-MLL Interaction in MLL Related Leukemias: Summary
Translocations of the MLL (Mixed Lineage Leukemia) gene are frequently found in human leukemias affecting both children and adults. Fusion of MLL to one of more than 60 genes results in generation of oncogenic proteins upregulating Hox genes, which are vital to blood cell development. Patients harboring fusion of the MLL gene suffer from aggressive leukemias and respond poorly to available more ..
qHTS Assay for Inhibitors Targeting the Menin-MLL Interaction in MLL Related Leukemias
NIH Chemical Genomics Center [NCGC]
NIH Molecular Libraries Probe Centers Network [MLPCN]
MLPCN Grant: MH084875-01A1
Assay Submitter (PI): Jolanta Grembecka, Tomasz Cierpicki, University of Virginia
Translocations of the MLL (Mixed Lineage Leukemia) gene are frequently found in human leukemias affecting both children and adults. Fusion of MLL to one of more than 60 genes results in generation of oncogenic proteins upregulating Hox genes, which are vital to blood cell development. Patients harboring fusion of the MLL gene suffer from aggressive leukemias and respond poorly to available therapies. All of the oncogenic fusion proteins have a preserved N-terminal fragment of MLL that has been identified to interact with menin. It has been recently discovered that association with menin is critical to the leukemogenic activity of the MLL fusion oncoproteins. Selective targeting of the menin-MLL interaction could provide an attractive therapeutic approach to develop novel drugs for MLL-related leukemias. Small molecules blocking the menin-MLL interaction should reverse the oncogenic potential of MLL fusion proteins.
We have developed and optimized a fluorescence polarization-based assay for the identification of Menin-MLL inhibitors. The assay was run employing two different MLL-derived peptides. The present assay uses a 12 amino acid peptide labeled with fluorescein at its N-terminus. This peptide consists of the menin high affinity binding motif from MLL and is potently bound by menin. Another peptide with a mutated sequence, labeled with Texas Red, was used in parallel as a less stringent screen for inhibitors.
This summary is written for the purposes of summarizing the probe activities from the project. At present, no compound activities have been confirmed from this project. Data shown are from primary screening results only.
MLSCN probes are given a score of 100. Molecules in the prior art are given a score of 80. Other, less active molecules in the same chemical series as the probe molecules are given a score of 50. Molecules pending validation are given a score of 10. Inactive analogues from these series are given a score of 0. The present results summarize results for select compounds chosen for validation in secondary assays.
Categorized Comment - additional comments and annotations
From MLP Probe Report:
Probe count: 1
MLP Probe ML# for probe 1: ML227
PubChem Substance ID (SID) for probe 1: 99432383
PubChem Compound ID (CID) for probe 1: 46926632
Probe type for probe 1: Inhibitor
IC50/EC50 (nM) for probe 1: 883
Target for probe 1: Menin-mll (gi: 18860839,56550039)
Anti-target for probe 1: None
NCBI Book chapter link for probe 1: http://www.ncbi.nlm.nih.gov/books/NBK133428/ (ID: 3025904)
Grant number for probe 1: MH084875-01A1
NCBI Book chapter title for probe 1: Inhibitors of the Menin-Mixed Lineage Leukemia (MLL) Interaction