The discovery of novel benzofuran-2-carboxylic acids as potent Pim-1 inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 21, Issue 10, 2011, Pages 3050-3056

  Xiang, Yibin ^a   Hirth, Bradford ^a   Asmussen, Gary ^a   Biemann, Hans Peter ^a   Bishop, Kimberly A ^a   Good, Andrew ^a   Fitzgerald, Maria ^a   Gladysheva, Tatiana ^a   Jain, Annuradha ^a   Jancsics, Katherine ^a   Liu, Jinyu ^a   Metz, Markus ^a   Papoulis, Andrew ^a   Skerlj, Renato ^a   Stepp, J David ^a   Wei, Ronnie R ^a  

^a GENZYME CORPORATION   (United States)

Author keywords

Amine; Basicity; Benzofuran; Carboxylic acid; Enzyme; Fragment screening; Hydrogen bond interaction; Inhibitor; Kinase; Medicinal chemistry; Salt bridge; SPR; Structure based design; Synthesis; X ray structure

Indexed keywords

BENZOFURAN 2 CARBOXYLIC ACID DERIVATIVE; CARBOXYLIC ACID DERIVATIVE; ENZYME INHIBITOR; PROTEIN KINASE PIM 1; PROTEIN KINASE PIM 2; PROTEIN SERINE THREONINE KINASE; UNCLASSIFIED DRUG;

ARTICLE; CRYSTAL STRUCTURE; DRUG STRUCTURE; ENZYME ASSAY; HYDROGEN BOND; IC 50; X RAY;

ANIMALS; BENZOFURANS; CARBOXYLIC ACIDS; CRYSTALLOGRAPHY, X-RAY; ENZYME ACTIVATION; ENZYME INHIBITORS; HUMANS; INHIBITORY CONCENTRATION 50; MICROSOMES, LIVER; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PROTO-ONCOGENE PROTEINS C-PIM-1; RATS;

EID: 79955556964     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2011.03.030     Document Type: Article

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22. Pim-1 protein was chemically minimally biotinylated with EZ-link Sulfo-NHS-LC-LC-biotin (Thermo Scientific) and removed of free biotin reagent by buffer exchanging 10 times with Amicon 3K Ultracel Membrane Ultra Centrifugal Filters (Millipore). All biosensor work was performed on a Biacore T100 instrument (GE Healthcare). NeutrAvidin (NA, Thermo Scientific) was amine coupled to the surface of a CM5 sensor chip to 8000-12,000 RU by standard methods. Biotinylated Pim-1 was captured onto the CM5-NA surface to 4000-6000 RU. Compounds were individually screened for binding at a final concentration of 75 μM at 4 °C. Steady-state affinities were determined for select compounds using similar assay conditions. Raw sensorgrams were double-referenced and solvent corrected with Biacore T100 Evaluation Software.
23. 2, Caliper Life Sciences, MA) and 150 μM ATP for Pim-1, 3 μM ATP for Pim-2 or 25 μM ATP for Pim-3 assay. The reaction was incubated at room temperature for 45 min for Pim-1, 90 min for Pim-2 and Pim-3 and terminated with a 100 mM Hepes pH 7.5 buffer containing 100 mM EDTA, 0.02% Brij, 0.1% CR-3 and 0.36% DMSO. The reaction product was detected by one cycle run on a LabChip 3000 (Caliper Life Sciences) using an off-chip mobility shift protocol.
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