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Discovery of Mer kinase inhibitors by virtual screening using Structural Protein-Ligand Interaction Fingerprints
C Da1, M Stashko1, C Jayakody1
1Center for Integrative Chemical Biology and Drug Discovery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, CB #7360, Chapel Hill, NC 27599-7363, United States.
Abstract:
Mer is a receptor tyrosine kinase implicated in acute lymphoblastic leukemia (ALL), the most common malignancy in children. The currently available data provide a rationale for development of Mer kinase inhibitors as cancer therapeutics that can target both cell autologous and immune-modulatory anti-tumor effects. We have previously reported several series of potent Mer inhibitors and the objective of the current report is to identify a chemically dissimilar back-up series that might circumvent potential, but currently unknown, flaws inherent to the lead series. To this end, we virtually screened a database of ∼3.8million commercially available compounds using high-throughput docking followed by a filter involving Structural Protein-Ligand Interaction Fingerprints (SPLIF). SPLIF permits a quantitative assessment of whether a docking pose interacts with the protein target similarly to an endogenous or known synthetic ligand, and therefore helps to improve both sensitivity and specificity with respect to the docking score alone. Of the total of 62 experimentally tested compounds, 15 demonstrated reliable dose-dependent responses in the Mer in vitro kinase activity assay with inhibitory potencies ranging from 0.46microM to 9.9microM.
Insights
Researchers identified new Mer kinase inhibitors for acute lymphoblastic leukemia (ALL) treatment. This discovery offers a promising alternative therapeutic strategy by targeting cancer cells and enhancing anti-tumor immunity.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Mer receptor tyrosine kinase is a key target in acute lymphoblastic leukemia (ALL).
- Existing Mer inhibitors show potential for both direct anti-cancer effects and immune modulation.
- A need exists for chemically distinct Mer inhibitor series to ensure robust therapeutic development.
Purpose of the Study:
- To identify a novel, chemically dissimilar series of Mer kinase inhibitors.
- To circumvent potential limitations of previously developed lead inhibitor series.
- To discover new therapeutic agents for acute lymphoblastic leukemia.
Main Methods:
- Utilized high-throughput virtual screening of approximately 3.8 million compounds.
- Employed docking simulations followed by Structural Protein-Ligand Interaction Fingerprints (SPLIF) analysis.
- Conducted in vitro kinase activity assays on 62 selected compounds.
Main Results:
- Identified 15 compounds with reliable dose-dependent Mer inhibitory activity.
- Achieved inhibitory potencies ranging from 0.46 microM to 9.9 microM.
- Validated the effectiveness of SPLIF filtering in enhancing virtual screening specificity.
Conclusions:
- Successfully identified a chemically distinct series of Mer kinase inhibitors.
- These novel inhibitors represent a viable back-up strategy for ALL therapeutic development.
- The findings support Mer kinase as a druggable target for pediatric leukemia.
