UNIT 3. CHEMISTRY The objective of Unit 3 is to advance Hit compounds to Probes that have sufficient potency, selectivity, physicochemical, and pharmacological properties to be useful as research tools. Our Chemistry Unit uses a full complement of approaches to design and synthesize optimized Probe compounds, including: (1) modern medicinal chemistry;(2) cheminformatics, and computational chemistry and modeling;(3) advanced microfluidic synthesis technology;(4) innovative NMR-based methods for compound optimization utilizing chemical fragment linking strategies;and (5) exploratory pharmacology including in vitro assays that help both triage hits early and assist with the compound optimization process. Altogether, the chemical synthesis and supporting capabilities of the Burnham Center are among the most diverse and advanced of the present MLSCN Centers. This proposal builds on the Chemistry Unit's strong performance during the MLSCN Phase. We describe progress to date and plans to undertake a minimum of 25 Probe production projects annually to improve the potency and optimize the physicochemical properties of Hit compounds, delivering at least 15 new Probes per year.

National Institute of Health (NIH)
National Human Genome Research Institute (NHGRI)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZRG1-IFCN-K)
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Sanford-Burnham Medical Research Institute
La Jolla
United States
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Pagano, Nicholas; Teriete, Peter; Mattmann, Margrith E et al. (2017) An integrated chemical biology approach reveals the mechanism of action of HIV replication inhibitors. Bioorg Med Chem 25:6248-6265
Barak, Larry S; Bai, Yushi; Peterson, Sean et al. (2016) ML314: A Biased Neurotensin Receptor Ligand for Methamphetamine Abuse. ACS Chem Biol 11:1880-90
Roy, Sudeshna; Šileikyt?, Justina; Neuenswander, Benjamin et al. (2016) N-Phenylbenzamides as Potent Inhibitors of the Mitochondrial Permeability Transition Pore. ChemMedChem 11:283-8
Schreiber, Stuart L; Kotz, Joanne D; Li, Min et al. (2015) Advancing Biological Understanding and Therapeutics Discovery with Small-Molecule Probes. Cell 161:1252-65
Tautz, Lutz; Senis, Yotis A; Oury, Cécile et al. (2015) Perspective: Tyrosine phosphatases as novel targets for antiplatelet therapy. Bioorg Med Chem 23:2786-97
Alontaga, Aileen Y; Li, Yifei; Chen, Chih-Hong et al. (2015) Design of high-throughput screening assays and identification of a SUMO1-specific small molecule chemotype targeting the SUMO-interacting motif-binding surface. ACS Comb Sci 17:239-46
Zou, Haixia; Limpert, Allison S; Zou, Jiwen et al. (2015) Benzodiazepinone derivatives protect against endoplasmic reticulum stress-mediated cell death in human neuronal cell lines. ACS Chem Neurosci 6:464-75
Rozanov, Dmitri; Cheltsov, Anton; Sergienko, Eduard et al. (2015) TRAIL-Based High Throughput Screening Reveals a Link between TRAIL-Mediated Apoptosis and Glutathione Reductase, a Key Component of Oxidative Stress Response. PLoS One 10:e0129566
Roy, Sudeshna; Šileikyt?, Justina; Schiavone, Marco et al. (2015) Discovery, Synthesis, and Optimization of Diarylisoxazole-3-carboxamides as Potent Inhibitors of the Mitochondrial Permeability Transition Pore. ChemMedChem 10:1655-71
Musumeci, Lucia; Kuijpers, Marijke J; Gilio, Karen et al. (2015) Dual-specificity phosphatase 3 deficiency or inhibition limits platelet activation and arterial thrombosis. Circulation 131:656-68

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