Discovery of Mer kinase inhibitors by virtual screening using Structural Protein–Ligand Interaction Fingerprints. Issue 5 (1st March 2015)

• Record Type: Journal Article
• Authors: Da, C.; Stashko, M.; Jayakody, C.; Wang, X.; Janzen, W.; Frye, S.; Kireev, D.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 5(2015)
• Page Start: 1096
• Page End: 1101
• Publication Date: 2015-03-01
• Subjects: Mer Mer tyrosine kinase -- ALL acute lymphoblastic leukemia -- VS virtual screening -- SPLIF Structural Protein–Ligand Interaction Fingerprints -- ECFP extended connectivity fingerprint; Mer tyrosine kinase -- Acute lymphoblastic leukemia -- Virtual screening -- Structural Protein–Ligand Interaction Fingerprints; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.01.001
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 ∼3.8 million 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 0.46 μM to 9.9 μM.