title: Discovery of Mer kinase inhibitors by virtual screening using Structural Protein-Ligand Interaction Fingerprints.
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 0.46μM to 9.9μM.
authors: Center 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.
authors: C
authors: C
authors: Da
authors: Center 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.
authors: M
authors: M
authors: Stashko
authors: Center 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.
authors: C
authors: C
authors: Jayakody
authors: Center 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.
authors: X
authors: X
authors: Wang
authors: Center 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.
authors: W
authors: W
authors: Janzen
authors: Center 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.
authors: S
authors: S
authors: Frye
authors: Center 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. Electronic address: dmitri.kireev@unc.edu.
authors: D
authors: D
authors: Kireev
mesh_terms: D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011786:Quality Control; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D047428:Protein Kinase Inhibitors; D020794:Receptor Protein-Tyrosine Kinases
keywords: Acute lymphoblastic leukemia; Mer tyrosine kinase; Structural Protein–Ligand Interaction Fingerprints; Virtual screening
references: Blood. 2009 Sep 24;114(13):2678-87
references: 19643988
references: J Comput Aided Mol Des. 2008 Mar-Apr;22(3-4):213-28
references: 18196462
references: J Med Chem. 2004 Mar 25;47(7):1739-49
references: 15027865
references: J Med Chem. 2004 Jun 3;47(12):3032-47
references: 15163185
references: J Med Chem. 2014 Aug 28;57(16):7031-41
references: 25068800
references: J Biomol Screen. 2007 Oct;12(7):972-82
references: 17942790
references: Proteins. 2004 Nov 1;57(2):225-42
references: 15340911
references: Eur J Med Chem. 2013 Jul;65:83-93
references: 23693152
references: J Chem Inf Model. 2014 Sep 22;54(9):2555-61
references: 25116840
references: Curr Comput Aided Drug Des. 2011 Jun;7(2):146-57
references: 21534921
references: J Chem Inf Model. 2012 Apr 23;52(4):867-81
references: 22435959
references: J Med Chem. 2006 Oct 5;49(20):5912-31
references: 17004707
references: J Chem Inf Model. 2007 Jul-Aug;47(4):1504-19
references: 17591764
references: Anticancer Agents Med Chem. 2009 Jan;9(1):66-76
references: 19149483
references: Angew Chem Int Ed Engl. 1999 Dec 16;38(24):3743-3748
references: 10649345
references: Nat Rev Drug Discov. 2004 Nov;3(11):935-49
references: 15520816
references: J Biomol Screen. 2004 Aug;9(5):409-16
references: 15296640
references: J Struct Biol. 2009 Feb;165(2):88-96
references: 19028587
references: J Med Chem. 2008 Apr 24;51(8):2432-8
references: 18380424
references: J Med Chem. 2013 Dec 12;56(23):9683-92
references: 24195762
references: N Engl J Med. 2004 Apr 8;350(15):1535-48
references: 15071128
references: ACS Med Chem Lett. 2012 Feb 9;3(2):129-134
references: 22662287
references: Clin Cancer Res. 2006 May 1;12(9):2662-9
references: 16675557
references: J Med Chem. 2004 Jan 15;47(2):337-44
references: 14711306
references: J Med Chem. 2013 Dec 12;56(23):9693-700
references: 24219778
references: Adv Drug Deliv Rev. 2002 Mar 31;54(3):255-71
references: 11922947
references: J Chem Inf Model. 2009 Jun;49(6):1455-74
references: 19476350
references: J Pharmacol Toxicol Methods. 2000 Jul-Aug;44(1):235-49
references: 11274893
references: Phys Chem Chem Phys. 2010 Oct 28;12(40):12899-908
references: 20730182