Shaun R. Stauffer,  PhD

Shaun R. Stauffer, PhD

Staff

Center Director and Director of Medicinal Chemistry

Lerner Research Institute, 9500 Euclid Avenue, Cleveland, Ohio 44195

 

Cleveland Clinic's Center for Therapeutics Discovery (C3TD) aids in the identification of promising hypotheses and targets with potential to address unmet medical need and shift the standard of care. To accomplish this task, Dr. Stauffer and C3TD teams partner with investigators to identify gaps and barriers preventing forward progress towards illuminating and redirecting translational research. The most promising C3TD projects progress into a development pipeline to support IND enabling studies that can be funded through multiple models, including accelerator partnership support, startup company initiated funding, or industry sponsored research agreements.

C3TD provides expertise and services in medicinal chemistry, protein science/structural biology, screening/target validation, and drug metabolism/pharmacokinetics. We employ a number of industrially proven technologies and approaches to obtain selective, potent, and patentable chemical entities, in addition to the preparation of prior art reference compounds to investigators. These activities aid to pave the path towards in vivo proof-of-concept in accepted preclinical models and add value through various gated risk reduction studies that inform the path towards development.

Dr. Stauffer has drug discovery experience leading industry and academic teams in several therapeutic areas, including neurodegenerative disease, cancer, and cardiovascular disease. He is a co-author on over 80 peer reviewed publications and has 28 issued US patents. His chemistry interests lie in the areas of catalysis and reaction discovery as tools for problem solving in medicinal chemistry and late lead optimization. His therapeutic and research interests are broad and include protein-protein interactions, epigenetic and metabolic drug targets, allosteric modulation, and structure-based design.


See publications for Shaun Stauffer, PhD, on PubMed.

20 most recent publications listed:

58) Conde-Ceide, S.; Martínez-Viturro, C. M.; Alcázar, J.; Garcia-Barrantes, P. M.; Lavreysen, H.; Mackie, C.; Vinson, P. N.; Rook, J. M.; Bridges, T. M.; Daniels, J. S.; Megens, A.; Langlois, X.; Drinkenburg, W. H.; Ahnaou, A.; Niswender, C. M.; Jones, C. K.; Macdonald, G. J.; Steckler, T.; Conn, P. J.; Stauffer, S. R.; Bartolomé-Nebreda, J. M.; Lindsley, C. W. Discovery of VU0409551/JNJ-46778212: An mGlu5 Positive Allosteric Modulator Clinical Candidate Targeting Schizophrenia. ACS Med. Chem. Lett. 2015,6, 716-720.

59) Schreiber, S. L.; Kotz, J. D.; Li, M.; Aube, J.; Austin, C. P.; Reed, J. C.; Rosen, H.; White, E. L.; Sklar, L. A.; Lindsley, C. W.; Alexander, B. R.; Bittker, J. A.; Clemons, P, A.; de Souza, A.; Foley, M. A.; Palmer, M.; Shamji, A.; Wawer, M. J.; Mcmanus, O. B.; Wu, M.; Zou, B.; Yu, H.; Golden, J. E.; Schoenen, F. J.; Pinkerton, A. B.; Chung, T. D.; Griffin, P. R. Cravatt, B. F.; Hodder, P. S.; Roush, W. R.; Roberts, E.; Chung, D.-H.; Jonsson, C.; Noah, J. W.; Severson, W. E.; Ananthan, S. A.; Edwards, B. S.; Oprea, T. I.; Conn, P. J.; Hopkins, C. R.; Wood, M. R.; Stauffer, S. R.; Emmitte, K. A.  Advancing Biological Understanding and Therapeutics Discovery with Small-Molecule Probes. Cell, 2015, 161, 1252-1265.

60) St. John, S. E.; Tomar, S.; Stauffer, S. R.; Mesecar, A. D. Targeting zoonotic viruses: structure-based inhibition of the 3C-like protease from bat coronavirus HKU4 - the likely reservoir host to the human coronavirus that causes Middle East Respiratory Syndrome (MERS). Bioorg. Med. Chem., 2015, 17, 6036-6048.

61) Zhou, Y.; Malosh, C.; Conde-Ceide, S.; Martínez-Viturro, C. M.; Alcázar, J.; Lavreysen, H.; Mackie, C.; Bridges, T. M.; Daniels, J. S.; Niswender, C. M.; Jones, C. K.; Macdonald, G. J.; Steckler, T.; Conn, P. J.; Stauffer, S. R.; Bartolomé-Nebreda, J. M.; Lindsley, C. L. Further optimization of the mGlu5 PAM clinical candidate VU0409551/JNJ-46778212: Progress and challenges towards a back-up compound.  Bioorg. Med. Chem. Lett., 2015,17, 3515-3519.

62) Egbertson, M.; McGaughey, G. B.; Pitzenberger, S. M.; Stauffer, S. R.; Coburn, C. A.; Stachel, S. J.; Yang, W.; Barrow, J. C.; Neilson, L. A.; McWherter, M.; Perlow, D.; Fahr, B.; Munshi, S.; Allison, T. A.; Holloway, K.; Selnick, H.; Yang, Z.; Swestock, J.; Simon, A. J.; Sankaranarayanan, S.; Colussi, D.; Tugusheva, K.; Lai, M.-T.; Pietrak, B.; Haugabook, S.; Jin, L.; Chen, I.-W.; Holahan, M.; Stranieri-Michener, M.; Cook, J. J.; Vacca, J.; Graham, S. L.  Methyl-substitution of an iminohydantoin spiropiperidine b-secretase (BACE-1) inhibitor has a profound effect on its potency. Bioorg. Med. Chem. Lett., 2015, 25, 4812-4819.

63) Ahowesso, C.; Black, P. N.; Saini, N.; Montefusco, D.; Chekal, J.; Malosh, C.; Lindsley, C. W.; Stauffer, S. R.; DiRusso, C. C. Chemical inhibition of fatty acid absorption and cellular uptake limits lipotoxic cell death. Biochemical Pharmacology, 2015, 98, 167-181.

64) Malosh, C.; Turlington, M.; Bridges, T. M.; Rook, J. M.; Noetzel, M. J.; Vinson, P. N.; Steckler, T.; Lavreysen, H.; Mackie, C.; Bartolomé-Nebreda, J. M.; Conde-Ceide, S.; Martínez-Viturro, C. M.; Piedrafita, M.; Sánchez-Casado, M. R.; Macdonald, G. J.; Daniels, J. S.; Jones, C. K.; Niswender, C. M.; Conn, P. J.; Lindsley, C. W.; Stauffer, S. R. Acyl dihydropyrazolo[1,5-a]pyrimidinones as metabotropic glutamate receptor 5 positive allosteric modulators.  Bioorg. Med. Chem. Lett. 2015, 25, 5115-5120.

65) Ghoshal, A.; Rook, J. M.; Dickerson, J. W.; Poslusney, M.; Roop, G. N.; Morrison, R.; Noetzel, M. N.; Stauffer, S. R.; Xiang, Z.; Daniels, S. J.; Niswender,  C. M.; Jones, C. K.; Lindsley, C. W.; Conn, P.J. Potentiation of M1 muscarinic receptors reverses plasticity deficits and negative and cognitive symptoms in a schizophrenia mouse model.  Nature Neuroscience, 2016, 41, 598-610.

66) Nickols, H. H.; Yuh, J. P.; Gregory, K. J.; Morrison, R. D.; Bates, B.; Stauffer, S. R.; Emmitte, K. A.; Bubser, M.; Peng, W.; Nedelcovych, M. T.; Thompson, A.;  Lv, X.; Xiang, Z.; Daniels, J. S.; Niswender, C. M.; Lindsley, C. W.; Jones, C. W.; Conn, P. J.   VU0477573: Partial negative allosteric modulator of the subtype 5 metabotropic glutamate receptor with in vivo efficacy.  J. Pharmacol. Exp. Ther. 2016, 356, 123-136.

67) Wu, Y.; Stauffer, S. R.; Stanfield, R. L.; Tapia, P. H.; Ursu, O.; Fisher, G. W.; Szent-Gyorgyi, C.; Evangelisti, A.; Waller, A.; Strouse, J. J.; Carter, M. B.; Bologa, C.; Gouveia, K.; Poslusney, M.; Waggoner, A. S.; Lindsley, C. W.; Jarvik, J. W.; Sklar, L. A. Discovery of Small-Molecule Nonfluorescent Inhibitors of Fluorogen–Fluorogen Activating Protein Binding Pair. J. Biomol. Screen., 2016, 21, 74-87.

68) Condé-Ceidé, S.; Alcazar, J.; Alonso de Deigo, S. A.; Lopéz, S.; Martín-Martín, M. L.; Martinez-Viturro, C. M.; Pena, M.-A.; Tong, H. M.; Lavreysen, H.; Mackie, C.; Bridges, T. M.; Daniels, J. S.; Niswender, C. M.; Jones, C. K.; Macdonald, G. J.; Steckler, T.; Conn, P. J.; Stauffer, S. R.; Lindsley, C. W.; Bartolomé-Nebreda, J. M. Preliminary investigation of 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one derivatives as a novel series of mGlu5 receptor positive allosteric modulators with efficacy in preclinical models of schizophrenia. Bioorg. Med. Chem. Lett., 2016, 25, 429-434.

69) Gogliotti, R. G.; Klar, R.; Rook, J. M.; Ghoshal, A.; Zamorano, R.; Malosh, C.; Stauffer, S. R.; Bridges, T. M.; Bartolome, J. M.; Daniels, J. S.; Jones, C.; Lindsley, C. W.; Conn, P. J.; Niswender, C. M.  mGlu5 Positive allosteric modulation normalizes synaptic plasticity defects and motor phenotypes in a mouse model of Rett Syndrome. Hum. Mol. Genet. 2016, 25, 1990-2004.

70) Temple, K. J.; Duverney, M. T.; Young, S. E.; Wen, W.; Wu, W.; Maeng, J. G.; Blobaum, A. L.; Stauffer, S. R.; Hamm, H.; Lindsley, C. W. Development of a Series of (1-Benzyl-3-(6-methoxypyrimidin-3-yl)-5-(trifluoromethoxy)-1H-indol-2-yl)methanols as Selective Protease Activated Receptor 4 (PAR4) Antagonists with in Vivo Utility and Activity Against g-Thrombin. J. Med. Chem.,2016, 59, 7690-7695.

71) Panarese, J. D.; Cho, H. P.; Adams, J. J.; Nance, K. D.; Garcia-Barrantes, P. M.; Chang, S.; Morrison, R. D.; Blobaum, A. L.; Niswender, C. M.; Stauffer, S. R.; Conn, P. J.; Lindsley, C. W. Further optimization of the M1 PAM VU0453595: Discovery of novel heterobicyclic core motifs with improved CNS penetration. Bioorg. Med. Chem. Lett.,2016, 26, 3822-3825.

72) Temple, K. J.; Duverney, M. T.; Maeng, J. G.; Blobaum, A. L.; Stauffer, S. R.; Hamm, H.; Lindsley, C. W. Identification of the minimum PAR4 inhibitor pharmacophore and optimization of a series of 2-methoxy-6-arylimidazo[2,1-b][1,3,4]thiadiazoles. Bioorg. Med. Chem. Lett.,2016, 26, 5481-5486.

73) Duverney, M. T.; Temple, K. J.; Maeng, J. G.; Blobaum, A. L.; Stauffer, S. R.; Hamm, H.; Lindsley, C. W. Contributions of PAR1 and PAR4 to thrombin induced GPIIbIIIa activation in human platelets. Mol. Pharm., 2017, 91, 39-47.

74) Ginnetti, A. T.; Paone, D. V.; Stauffer, S. R.; Potteiger, C. M.; Shaw, A. W.; Deng, J.; Mulhearn, J. J.; Nguyen, D. N.; Segerdell, C.; Anquandah, J.; Calamari, A.; Cheng, G.; Leitl, M. D.; Liang, A.; Moore, E.; Panigel, J.; Urban, M.; Wang, J.; Fillgrove, K.; Tang, C.; Cook, S.; Kane, S.; Salvatore, C. A.; Graham, S. L.; Burgey, C. S. Identification of second-generation P2X3 antagonists for treatment of pain. Bioorg. Med. Chem. Lett., 2018, 28, 1392-1396.

75) Rook, J. M.; Bertron, J. L.; Cho, H. P.; Garcia-Barrantes, P. M.; Moran, S. P.; Maksymetz, J. T.; Nance, K. D.; Dickerson, J. W.; Remke, D. H.; Chang, S.; Harp, J.; Blobaum, A. L.; Niswender, C. M.; Jones, C. K.; Stauffer, S. R.; Conn, P. J.; Lindsley, C. W. A novel M1 PAM VU0486846 exerts efficacy in cognition models without displaying agonist activity or cholinergic toxicity.  ACS Chem. Neuro., 2018, Ahead of print, DOI:10.1021/acschemneuro.8b00131.

76) Bertron, J. L.; Cho, H. P.; Garcia-Barrantes, P. M.; Panarese, J. D.; Salovich, J. M.; Nance, K. D.; Engers, D. W.; Rook, J. M.; Blobaum, A. L.; Niswender, C. M.; Stauffer, S. R.; Conn, P. J.; Lindsley, C. W. The discovery of VU0486846:  steep SAR from a series of M1 PAMs based on a novel benzomorpholine core. Bioorg. Med. Chem. Lett., 2018, 28, 2175-2179.

77) Wang, F.; Jeon, K. O.; Salovich, J. M.; Macdonald, J. D.; Alvarado, J.; Gogliotti, R. D.; Phan, J.; Olejniczak, E. T.; Sun, Q.; Wang, S.; Camper, D.; Yuh, J. P.; Shaw, G.; Sai, J.; Rossanese, O. W.; Tansey, W. P.; Stauffer, S. R.; Fesik, S. W. Discovery of Potent 2-Aryl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazoles as WDR5-WIN Site Inhibitors Using Fragment-Based Methods and Structure-Based Design.  J. Med. Chem. 2018, 61, 5623-5642.

78) Aho, E. R.; Wang, J.; Gogliotti, R. D.; Howard, G. C.; Phan, J.; Acharya, P.; Macdonald, J. D.; Cheng, K.; Lorey S. L.; Lu, B.; Wenzel, S.; Foshage, A. M.; Alvarado, J.; Wang, F.; Shaw, J. G.; Zhao, B.; Weissmiller, A. M.; Thomas, L. R.; Vakoc, C. R.; Hall, M. D.; Hiebert, S. W.; Liu, Q.; Stauffer, S. R.; Fesik S. W.; Tansey, W. P.  Displacement of WDR5 from Chromatin by a WIN Site Inhibitor with Picomolar Affinity. Cell Reports, 2019, 26, 2916-2928.


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