Research Summary
Dr. Barrow’s laboratory is focused on medicinal chemistry approaches to address diseases of neurodevelopment such as schizophrenia. Biological activity and structure-based drug design are used to drive chemistry target selection, and we are developing synthetic methods to efficiently prepare those targets. These efforts are tightly coupled with in vitro and in vivo testing and analysis, in collaboration with other research groups and core facilities at Johns Hopkins University or externally.
At the core, the lab is engaged in the design and synthesis of molecules for a given biological target, analysis of in vitro and in vivo results, as well as further refinement through multiple cycles of synthesis and testing. Advances in reaction methodology, reagent availability, parallel synthesis, and purification technology now allow preparation of compounds in an efficient manner so that we can quickly drive structure-activity relationship studies and identify advanced leads. These advanced leads will have good potency and selectivity for the target of interest, and will be used to test biological hypotheses both in vitro and in vivo to determine if modulating the target is indeed a viable therapeutic strategy. By executing on medicinal chemistry programs, the lab will drive translational science from target and pathway discovery to novel medicines for patients.
Selected Publications
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Colis L, Ernst G, Sanders S, Liu H, Sirajuddin P, Peltonen K, DePasquale, M, Barrow JC, Laiho, M. Design, Synthesis, and Structure−Activity Relationships of Pyridoquinazolinecarboxamides as RNA Polymerase I Inhibitors. J. Med. Chem. 2014; 157: 4950.
Rao F, Xu J, Fu C, Cha J, Gadalla M, Xu R, Barrow JC, Snyder SH. Inositol pyrophosphates promote tumor growth and metastasis by antagonizing liver kinase B1. Proc. Nat. Acad. Sci. 2015; 112: 1773. PMID: 25617365
Harrison ST, Poslusney MS, Mulhearn JJ, Zhao Z, Kett NR, Schubert JW, Melamed JY, Allison TJ, Patel S, Sanders JM, Sharma S, Smith RF, Hall DL, Robinson RG, Sachs NA, Hutson PH, Wolkenberg SE, Barrow JC. Synthesis and Evaluation of Heterocyclic Catechol Mimics as Inhibitors of Catechol-O-methyltransferase (COMT). ACS Med. Chem. Lett. 2015, 6, 318.
Uslaner JM, Smith SM, Huszar SL, Pachmerhiwala R, Hinchliffe RM, Vardigan JD, Nguyen SJ, Surles NO, Yao L, Barrow JC, Uebele VN, Renger JJ, Clark J, Hutson PH. T-type calcium channel antagonism produces antipsychotic-like effects and reduces stimulant-induced glutamate release in the nucleus accumbens of rats. Neuropharmacology 2012:62:1413
Calcaterra NE, Hoeppner DJ, Wei H, Jaffe AE, Maher BJ, Barrow JC. Schizophrenia-Associated hERG channel Kv11.1-3.1 Exhibits a Unique Trafficking Deficit that is Rescued through Proteasome Inhibition for High Throughput Screening. Sci Rep. 2016, 6, 19976.
