Department of Pharmacology

Faculty

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Shaun R Stauffer, Ph.D.

Research Assistant Professor of Pharmacology
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shaun.stauffer@Vanderbilt.Edu
615-936-8407
12415-D MRBIV-Langford
Nashville, TN 37232-6600

Education

NIH Postdoctoral Fellow, Yale University, New Haven, CT
Ph.D., University of Illinois, Urbana, IL
B.S., Southern Illinois University, Carbondale, IL

Research Keywords

Drug discovery, medicinal chemistry, allosteric modulation, structure-based design, protein-protein interaction (PPI) modulators, GPCRs, proteases, organometallic catalysis, reaction discovery, high-throughput experimentation (HTE), schizophrenia, Alzheimers disease, oncology

Research Description

Dr. Stauffer's research interests lie in the areas of allosteric modulation of cell surface receptors, protein-protein interaction (PPI) modulation, and protease structure-based inhibitor design towards the development of novel therapeutics and selective probe tool compounds.

In addition, Dr. Stauffer is interested in catalysis and reaction discovery using high-throughput experimentation (HTE) methods and its application towards enabling novel library syntheses and utility in addressing challenges in hypothesis driven medicinal chemistry.

Dr. Stauffer served as co-director within the Vanderbilt Specialized Chemistry Center for Accelerated Probe Development, (MLPCN, 2008-2014) and oversaw the development of over a dozen probe molecules, many leading to in vivo POC studies. In addition, during this time Dr. Stauffer co-led a J&J (Janssen) sponsored drug discovery team within the Center for Neuroscience Drug Discovery focusing on novel small molecule positive allosteric modulators of the metabotropic glutamate receptor 5 for the treatment of schizophrenia, leading to NME candidate selection and a subsequent backup program (2009-2012).

Dr. Stauffer currently serves as associate director of medicinal chemistry within the VICB SynCore and is involved in several collaborative projects within the Fesik (PPIs, structure-guided fragment based drug discovery) and Hamm (Gbg-SNARE, PAR4 antagonists) laboratories.

Publications

Han, C, Chatterjee, A, Noetzel, MJ, Panarese, JD, Smith, E, Chase, P, Hodder, P, Niswender, C, Jeffrey Conn, P, Lindsley, CW, Stauffer, SR. Discovery and SAR of muscarinic receptor subtype 1 (M1) allosteric activators from a molecular libraries high throughput screen. Part 1: 2,5-Dibenzyl-2H-pyrazolo[4,3-c]quinolin-3(5H)-ones as positive allosteric modulators. Bioorg Med Chem Lett, 25(2), 384-8, 2015

Gregory, KJ, Nguyen, ED, Malosh, C, Mendenhall, JL, Zic, JZ, Bates, BS, Noetzel, MJ, Squire, EF, Turner, EM, Rook, JM, Emmitte, KA, Stauffer, SR, Lindsley, CW, Meiler, J, Conn, PJ. Identification of specific ligand-receptor interactions that govern binding and cooperativity of diverse modulators to a common metabotropic glutamate receptor 5 allosteric site. ACS Chem Neurosci, 5(4), 282-95, 2014

D''Amore, V, Santolini, I, Celli, R, Lionetto, L, De Fusco, A, Simmaco, M, van Rijn, CM, Vieira, E, Stauffer, SR, Conn, PJ, Bosco, P, Nicoletti, F, van Luijtelaar, G, Ngomba, RT. Head-to head comparison of mGlu1 and mGlu5 receptor activation in chronic treatment of absence epilepsy in WAG/Rij rats. Neuropharmacology, 85, 91-103, 2014

Turlington, M, Malosh, C, Jacobs, J, Manka, JT, Noetzel, MJ, Vinson, PN, Jadhav, S, Herman, EJ, Lavreysen, H, Mackie, C, Bartolom??-Nebreda, JM, Conde-Ceide, S, Mart??n-Mart??n, ML, Tong, HM, L??pez, S, MacDonald, GJ, Steckler, T, Daniels, JS, Weaver, CD, Niswender, CM, Jones, CK, Conn, PJ, Lindsley, CW, Stauffer, SR. Tetrahydronaphthyridine and dihydronaphthyridinone ethers as positive allosteric modulators of the metabotropic glutamate receptor 5 (mGlu???). J Med Chem, 57(13), 5620-37, 2014

Turlington, M, Noetzel, MJ, Bridges, TM, Vinson, PN, Steckler, T, Lavreysen, H, Mackie, C, Bartolom??-Nebreda, JM, Conde-Ceide, S, Tong, HM, Macdonald, GJ, Daniels, JS, Jones, CK, Niswender, CM, Conn, PJ, Lindsley, CW, Stauffer, SR. Discovery and SAR of a novel series of metabotropic glutamate receptor 5 positive allosteric modulators with high ligand efficiency. Bioorg Med Chem Lett, 24(15), 3641-6, 2014

Wen, W, Young, SE, Duvernay, MT, Schulte, ML, Nance, KD, Melancon, BJ, Engers, J, Locuson, CW, Wood, MR, Daniels, JS, Wu, W, Lindsley, CW, Hamm, HE, Stauffer, SR. Substituted indoles as selective protease activated receptor 4 (PAR-4) antagonists: Discovery and SAR of ML354. Bioorg Med Chem Lett, 24(19), 4708-13, 2014

Rook, JM, Tantawy, MN, Ansari, MS, Felts, AS, Stauffer, SR, Emmitte, KA, Kessler, RM, Niswender, CM, Daniels, JS, Jones, CK, Lindsley, CW, Conn, PJ. Relationship between In Vivo Receptor Occupancy and Efficacy of Metabotropic Glutamate Receptor Subtype 5 Allosteric Modulators with Different In Vitro Binding Profiles. Neuropsychopharmacology, 2014

Jacobs, J, Grum-Tokars, V, Zhou, Y, Turlington, M, Saldanha, SA, Chase, P, Eggler, A, Dawson, ES, Baez-Santos, YM, Tomar, S, Mielech, AM, Baker, SC, Lindsley, CW, Hodder, P, Mesecar, A, Stauffer, SR. Discovery, synthesis, and structure-based optimization of a series of N-(tert-butyl)-2-(N-arylamido)-2-(pyridin-3-yl) acetamides (ML188) as potent noncovalent small molecule inhibitors of the severe acute respiratory syndrome coronavirus (SARS-CoV) 3CL protease. J Med Chem, 56(2), 534-46, 2013

Schulte, ML, Turlington, ML, Phatak, SS, Harp, JM, Stauffer, SR, Lindsley, CW. Total Synthesis of Stemaphylline N-Oxide and Related C9a-Epimeric Analogues. Chemistry, 2013

Gregory, KJ, Herman, EJ, Ramsey, AJ, Hammond, AS, Byun, NE, Stauffer, SR, Manka, JT, Jadhav, S, Bridges, TM, Weaver, CD, Niswender, CM, Steckler, T, Drinkenburg, WH, Ahnaou, A, Lavreysen, H, Macdonald, GJ, Bartolom??, JM, Mackie, C, Hrupka, BJ, Caron, MG, Daigle, TL, Lindsley, CW, Conn, PJ, Jones, CK. N-aryl piperazine metabotropic glutamate receptor 5 positive allosteric modulators possess efficacy in preclinical models of NMDA hypofunction and cognitive enhancement. J Pharmacol Exp Ther, 347(2), 438-57, 2013

Blobaum, AL, Bridges, TM, Byers, FW, Turlington, ML, Mattmann, ME, Morrison, RD, Mackie, C, Lavreysen, H, Bartolom??, JM, Macdonald, GJ, Steckler, T, Jones, CK, Niswender, CM, Conn, PJ, Lindsley, CW, Stauffer, SR, Daniels, JS. Heterotropic activation of the midazolam hydroxylase activity of CYP3A by a positive allosteric modulator of mGlu5: in vitro to in vivo translation and potential impact on clinically relevant drug-drug interactions. Drug Metab Dispos, 41(12), 2066-75, 2013

Turlington, M, Noetzel, MJ, Chun, A, Zhou, Y, Gogliotti, RD, Nguyen, ED, Gregory, KJ, Vinson, PN, Rook, JM, Gogi, KK, Xiang, Z, Bridges, TM, Daniels, JS, Jones, C, Niswender, CM, Meiler, J, Conn, PJ, Lindsley, CW, Stauffer, SR. Exploration of allosteric agonism structure-activity relationships within an acetylene series of metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs): discovery of 5-((3-fluorophenyl)ethynyl)-N-(3-methyloxetan-3-yl)picolinamide (ML254). J Med Chem, 56(20), 7976-96, 2013

Turlington, M, Chun, A, Tomar, S, Eggler, A, Grum-Tokars, V, Jacobs, J, Daniels, JS, Dawson, E, Saldanha, A, Chase, P, Baez-Santos, YM, Lindsley, CW, Hodder, P, Mesecar, AD, Stauffer, SR. Discovery of N-(benzo[1,2,3]triazol-1-yl)-N-(benzyl)acetamido)phenyl) carboxamides as severe acute respiratory syndrome coronavirus (SARS-CoV) 3CLpro inhibitors: identification of ML300 and noncovalent nanomolar inhibitors with an induced-fit binding. Bioorg Med Chem Lett, 23(22), 6172-7, 2013

Lindsley, CW, Stauffer, SR. Metabotropic glutamate receptor 5-positive allosteric modulators for the treatment of schizophrenia (2004-2012). Pharm Pat Anal, 2(1), 93-108, 2013

Noetzel, MJ, Gregory, KJ, Vinson, PN, Manka, JT, Stauffer, SR, Lindsley, CW, Niswender, CM, Xiang, Z, Conn, PJ. A novel metabotropic glutamate receptor 5 positive allosteric modulator acts at a unique site and confers stimulus bias to mGlu5 signaling. Mol Pharmacol, 83(4), 835-47, 2013

Gregory, KJ, Nguyen, ED, Reiff, SD, Squire, EF, Stauffer, SR, Lindsley, CW, Meiler, J, Conn, PJ. Probing the metabotropic glutamate receptor 5 (mGlu???) positive allosteric modulator (PAM) binding pocket: discovery of point mutations that engender a &quot;molecular switch&quot; in PAM pharmacology. Mol Pharmacol, 83(5), 991-1006, 2013

Rook, JM, Noetzel, MJ, Pouliot, WA, Bridges, TM, Vinson, PN, Cho, HP, Zhou, Y, Gogliotti, RD, Manka, JT, Gregory, KJ, Stauffer, SR, Dudek, FE, Xiang, Z, Niswender, CM, Daniels, JS, Jones, CK, Lindsley, CW, Conn, PJ. Unique signaling profiles of positive allosteric modulators of metabotropic glutamate receptor subtype 5 determine differences in in vivo activity. Biol Psychiatry, 73(6), 501-9, 2013

Bridges, TM, Rook, JM, Noetzel, MJ, Morrison, RD, Zhou, Y, Gogliotti, RD, Vinson, PN, Xiang, Z, Jones, CK, Niswender, CM, Lindsley, CW, Stauffer, SR, Conn, PJ, Daniels, JS. Biotransformation of a novel positive allosteric modulator of metabotropic glutamate receptor subtype 5 contributes to seizure-like adverse events in rats involving a receptor agonism-dependent mechanism. Drug Metab Dispos, 41(9), 1703-14, 2013

Kiritoshi, T, Sun, H, Ren, W, Stauffer, SR, Lindsley, CW, Conn, PJ, Neugebauer, V. Modulation of pyramidal cell output in the medial prefrontal cortex by mGluR5 interacting with CB1. Neuropharmacology, 2012

Gregory, KJ, Noetzel, MJ, Rook, JM, Vinson, PN, Stauffer, SR, Rodriguez, AL, Emmitte, KA, Zhou, Y, Chun, AC, Felts, AS, Chauder, BA, Lindsley, CW, Niswender, CM, Conn, PJ. Investigating metabotropic glutamate receptor 5 allosteric modulator cooperativity, affinity, and agonism: enriching structure-function studies and structure-activity relationships. Mol Pharmacol, 82(5), 860-75, 2012

D''Amore, V, Santolini, I, van Rijn, CM, Biagioni, F, Molinaro, G, Prete, A, Conn, PJ, Lindsley, CW, Zhou, Y, Vinson, PN, Rodriguez, AL, Jones, CK, Stauffer, SR, Nicoletti, F, van Luijtelaar, G, Ngomba, RT. Potentiation of mGlu5 receptors with the novel enhancer, VU0360172, reduces spontaneous absence seizures in WAG/Rij rats. Neuropharmacology, 2012

Sheffler, DJ, Wenthur, CJ, Bruner, JA, Carrington, SJ, Vinson, PN, Gogi, KK, Blobaum, AL, Morrison, RD, Vamos, M, Cosford, ND, Stauffer, SR, Daniels, JS, Niswender, CM, Conn, PJ, Lindsley, CW. Development of a novel, CNS-penetrant, metabotropic glutamate receptor 3 (mGlu3) NAM probe (ML289) derived from a closely related mGlu5 PAM. Bioorg Med Chem Lett, 22(12), 3921-5, 2012

Manka, JT, Vinson, PN, Gregory, KJ, Zhou, Y, Williams, R, Gogi, K, Days, E, Jadhav, S, Herman, EJ, Lavreysen, H, Mackie, C, Bartolom??, JM, Macdonald, GJ, Steckler, T, Daniels, JS, Weaver, CD, Niswender, CM, Jones, CK, Conn, PJ, Lindsley, CW, Stauffer, SR. Optimization of an ether series of mGlu5 positive allosteric modulators: molecular determinants of MPEP-site interaction crossover. Bioorg Med Chem Lett, 22(20), 6481-5, 2012

Noetzel, MJ, Rook, JM, Vinson, PN, Cho, HP, Days, E, Zhou, Y, Rodriguez, AL, Lavreysen, H, Stauffer, SR, Niswender, CM, Xiang, Z, Daniels, JS, Jones, CK, Lindsley, CW, Weaver, CD, Conn, PJ. Functional impact of allosteric agonist activity of selective positive allosteric modulators of metabotropic glutamate receptor subtype 5 in regulating central nervous system function. Mol Pharmacol, 81(2), 120-33, 2012

Rodriguez, AL, Zhou, Y, Williams, R, David Weaver, C, Vinson, PN, Dawson, ES, Steckler, T, Lavreysen, H, Mackie, C, Bartolom??, JM, Macdonald, GJ, Scott Daniels, J, Niswender, CM, Jones, CK, Jeffrey Conn, P, Lindsley, CW, Stauffer, SR. Discovery and SAR of a novel series of non-MPEP site mGlu??? PAMs based on an aryl glycine sulfonamide scaffold. Bioorg Med Chem Lett, 22(24), 7388-92, 2012

Stauffer, SR. Progress toward positive allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGlu???). ACS Chem Neurosci, 2(8), 450-70, 2011

Williams, R, Manka, JT, Rodriguez, AL, Vinson, PN, Niswender, CM, Weaver, CD, Jones, CK, Conn, PJ, Lindsley, CW, Stauffer, SR. Synthesis and SAR of centrally active mGlu5 positive allosteric modulators based on an aryl acetylenic bicyclic lactam scaffold. Bioorg Med Chem Lett, 21(5), 1350-3, 2011

Zhou, Y, Manka, JT, Rodriguez, AL, Weaver, CD, Days, EL, Vinson, PN, Jadhav, S, Hermann, EJ, Jones, CK, Conn, PJ, Lindsley, CW, Stauffer, SR. Discovery of N-Aryl Piperazines as Selective mGlu(5) Potentiators with Efficacy in a Rodent Model Predictive of Anti-Psychotic Activity. ACS Med Chem Lett, 1(8), 433-438, 2010

Rodriguez, AL, Grier, MD, Jones, CK, Herman, EJ, Kane, AS, Smith, RL, Williams, R, Zhou, Y, Marlo, JE, Days, EL, Blatt, TN, Jadhav, S, Menon, UN, Vinson, PN, Rook, JM, Stauffer, SR, Niswender, CM, Lindsley, CW, Weaver, CD, Conn, PJ. Discovery of novel allosteric modulators of metabotropic glutamate receptor subtype 5 reveals chemical and functional diversity and in vivo activity in rat behavioral models of anxiolytic and antipsychotic activity. Mol Pharmacol, 78(6), 1105-23, 2010

Uebele, VN, Nuss, CE, Santarelli, VP, Garson, SL, Kraus, RL, Barrow, JC, Stauffer, SR, Koblan, KS, Renger, JJ, Aton, S, Seibt, J, Dumoulin, M, Jha, SK, Coleman, T, Frank, MG. T-type calcium channels regulate cortical plasticity in-vivo. [corrected]. Neuroreport, 20(3), 257-62, 2009

Nantermet, PG, Rajapakse, HA, Stanton, MG, Stauffer, SR, Barrow, JC, Gregro, AR, Moore, KP, Steinbeiser, MA, Swestock, J, Selnick, HG, Graham, SL, McGaughey, GB, Colussi, D, Lai, MT, Sankaranarayanan, S, Simon, AJ, Munshi, S, Cook, JJ, Holahan, MA, Michener, MS, Vacca, JP. Evolution of tertiary carbinamine BACE-1 inhibitors: Abeta reduction in rhesus CSF upon oral dosing. ChemMedChem, 4(1), 37-40, 2009

Deng, JZ, Paone, DV, Ginnetti, AT, Kurihara, H, Dreher, SD, Weissman, SA, Stauffer, SR, Burgey, CS. Copper-facilitated Suzuki reactions: application to 2-heterocyclic boronates. Org Lett, 11(2), 345-7, 2009

Barrow, JC, Stauffer, SR, Rittle, KE, Ngo, PL, Yang, Z, Selnick, HG, Graham, SL, Munshi, S, McGaughey, GB, Holloway, MK, Simon, AJ, Price, EA, Sankaranarayanan, S, Colussi, D, Tugusheva, K, Lai, MT, Espeseth, AS, Xu, M, Huang, Q, Wolfe, A, Pietrak, B, Zuck, P, Levorse, DA, Hazuda, D, Vacca, JP. Discovery and X-ray crystallographic analysis of a spiropiperidine iminohydantoin inhibitor of beta-secretase. J Med Chem, 51(20), 6259-62, 2008

Stauffer, SR, Stanton, MG, Gregro, AR, Steinbeiser, MA, Shaffer, JR, Nantermet, PG, Barrow, JC, Rittle, KE, Collusi, D, Espeseth, AS, Lai, MT, Pietrak, BL, Holloway, MK, McGaughey, GB, Munshi, SK, Hochman, JH, Simon, AJ, Selnick, HG, Graham, SL, Vacca, JP. Discovery and SAR of isonicotinamide BACE-1 inhibitors that bind beta-secretase in a N-terminal 10s-loop down conformation. Bioorg Med Chem Lett, 17(6), 1788-92, 2007

Stanton, MG, Stauffer, SR, Gregro, AR, Steinbeiser, M, Nantermet, P, Sankaranarayanan, S, Price, EA, Wu, G, Crouthamel, MC, Ellis, J, Lai, MT, Espeseth, AS, Shi, XP, Jin, L, Colussi, D, Pietrak, B, Huang, Q, Xu, M, Simon, AJ, Graham, SL, Vacca, JP, Selnick, H. Discovery of isonicotinamide derived beta-secretase inhibitors: in vivo reduction of beta-amyloid. J Med Chem, 50(15), 3431-3, 2007

Stauffer, SR. Small molecule inhibition of the Bcl-X(L)-BH3 protein-protein interaction: proof-of-concept of an in vivo chemopotentiator ABT-737. Curr Top Med Chem, 7(10), 961-5, 2007

McGaughey, GB, Colussi, D, Graham, SL, Lai, MT, Munshi, SK, Nantermet, PG, Pietrak, B, Rajapakse, HA, Selnick, HG, Stauffer, SR, Holloway, MK. Beta-secretase (BACE-1) inhibitors: accounting for 10s loop flexibility using rigid active sites. Bioorg Med Chem Lett, 17(4), 1117-21, 2007

Barrow, JC, Nantermet, PG, Stauffer, SR, Ngo, PL, Steinbeiser, MA, Mao, SS, Carroll, SS, Bailey, C, Colussi, D, Bosserman, M, Burlein, C, Cook, JJ, Sitko, G, Tiller, PR, Miller-Stein, CM, Rose, M, McMasters, DR, Vacca, JP, Selnick, HG. Synthesis and evaluation of imidazole acetic acid inhibitors of activated thrombin-activatable fibrinolysis inhibitor as novel antithrombotics. J Med Chem, 46(25), 5294-7, 2003

Stauffer, SR, Hartwig, JF. Fluorescence resonance energy transfer (FRET) as a high-throughput assay for coupling reactions. Arylation of amines as a case study. J Am Chem Soc, 125(23), 6977-85, 2003

Stauffer, SR, Huang, Y, Coletta, CJ, Tedesco, R, Katzenellenbogen, JA. Estrogen pyrazoles: defining the pyrazole core structure and the orientation of substituents in the ligand binding pocket of the estrogen receptor. Bioorg Med Chem, 9(1), 141-50, 2001

Stambuli, JP, Stauffer, SR, Shaughnessy, KH, Hartwig, JF. Screening of homogeneous catalysts by fluorescence resonance energy transfer. Identification of catalysts for room-temperature Heck reactions. J Am Chem Soc, 123(11), 2677-8, 2001

Stauffer, SR, Huang, YR, Aron, ZD, Coletta, CJ, Sun, J, Katzenellenbogen, BS, Katzenellenbogen, JA. Triarylpyrazoles with basic side chains: development of pyrazole-based estrogen receptor antagonists. Bioorg Med Chem, 9(1), 151-61, 2001

Stauffer, SR, Beare, NA, Stambuli, JP, Hartwig, JF. Palladium-catalyzed arylation of ethyl cyanoacetate. Fluorescence resonance energy transfer as a tool for reaction discovery. J Am Chem Soc, 123(19), 4641-2, 2001