Raymon E. and Rosellen M. Lawton Distinguished Scholar in Chemistry
Adjunct Professor of Biochemistry
Ph.D. University of California at Berkeley, 2002
(Biological Chemistry, Catalysis)
The Chemical Biology of Signal Transduction
Cells use an elaborate network of signal transduction proteins to sense and respond to their environment. The Maly group aims to understand the enzyme families that are involved in these signaling events. The final goal of these studies is to identify new molecular targets for the treatment of human disease. We integrate techniques from organic chemistry, biochemistry, structural biology, proteomics, and cell biology to develop new tools that provide a greater understanding of diverse signaling processes. Our technological innovations seek to address the limitations of currently existing methods for studying these highly dynamic cellular events. Furthermore, we are using these tools to answer a number of fundamental questions in biology.
All of the projects in the Maly group attempt to answer questions that chemical tools are uniquely positioned to address. For example, we have developed a new method for controlling the activities of signaling enzymes with a cell permeable small molecule. This methodology has been applied to the study of GTPases because there is a dearth of effective pharmacological agents for studying these important and dynamic signaling proteins. Other projects in the lab seek to address the ongoing challenge of drug target validation. One of these projects involves the generation of potent and selective bivalent kinase inhibitors. These reagents allow the phenotypic effects of selectively inhibiting a particular kinase to be rapidly determined. Furthermore, this methodology is being used to uncover the subcellular functions of several clinically-relevant kinases during specific signaling events. Another project seeks to determine which kinase activities are misregulated in human cancer cell models with a general set of molecular probes. By profiling the full complement of kinase activities in cells, we hope to identify and validate new kinase drug targets. Finally, we are developing pharmacological agents that target specific parasite protein kinases in T. gondii, C. parvum, and P. falciparum. We not only hope to validate these kinases as attractive drug targets in these organisms but to develop advanced drug leads for the treatment of cryptosporidiosis, toxoplasmosis, and malaria.
Rose, J. C.; Stephany, J. J.; Wei, C. T.; ^Fowler D. M.; ^Maly, D. J. “Rapidly inducible Cas9 and DSB-ddPCR to probe editing kinetics” ACS Chem. Biol. 2017, 12, in press.
Rose, J. C.; Huang, P-S.; Camp, N. D.; Ye, J.; Leidal, A. M.; Goreshnik, I.; Trevillian, B. M.; Dickinson, M. S.; Cunningham-Bryant, D.; Debnath, J.; Baker, D.; Wolf-Yadlin, A.; Maly, D. J. “A computationally engineered RAS rheostat reveals RAS/ERK signaling dynamics” Nat. Chem. Biol. 2017, 13, 119-26.
Rose, J. C.; Stephany, J. J.; Valente, W. J..; ^Fowler D. M.; ^Maly, D. J., Dang, H. V.; Bielas, J. H. “Rapidly inducible Cas9 and DSB-ddPCR to probe editing kinetics” Nat. Methods. 2017, 14, 891-896.
Morita, S.; Villalta, S. A.; Feldman, H. C.; Register, A. C.; Rosenthal, W.; Hoffmann-Petersen, I. T.; Mehdizadeh, M.; Ghosh, R.; Wang, L.; Colon-Negron, K.; Meza-Acevedo, R.; Backes, B. J.; ^Maly, D. J.; ^Bluestone, J. A.; ^Papa, F. R. “Targeting ABL-IRE1α signaling spares ER-stressed pancreatic β-cells to reverse autoimmune diabetes” Cell Metab. 2017, 25, 883-97.
Feldman, H. C.; Tong, M.; Wang, l.; Meza-Acevedo, R.; Gobillot, T. A.; Lebedev, I.; Gliedt, M. J. Hari, S. B.; Mitra, A. K.; Backes, B. J.; Papa, F. R.; Seeliger, M. A.; Maly, D. J. “Structural and Functional Analysis of the Allosteric Inhibition of IRE1α with ATP-Competitive Ligands” ACS Chem. Biol. 2016, 11, 2195-205.
Gower, C. M.; Thomas, J. R.; Harrington, E.; Murphy, J.; Chang, M. E. K.; Cornella-Taracido, I.; Jain, R. K.; Schirle, M.; Maly, D. J. “Conversion of a single polypharmacological agent into selective bivalent inhibitors of intracellular kinase activity” ACS Chem. Biol. 2016, 11, 121-131.
Leonard, S. E.; Register, A. C.; Brighty, G. J.; Krishnamurty, R.; Maly, D. J. “Divergent Modulation of Src-Family Kinase Regulatory Interactions with ATP-Competitive Inhibitors.” ACS Chem. Biol. 2014, 9, 1894-905.
Krishnamurty, R.; Brigham, J. L.; Leonard, S. E.; Ranjitkar, P.; Dale, E. J.; Larson, E. T.; Merritt, E. A.; Maly, D. J. “Active site profiling reveals coupling between domains in SRC-family kinases.” Nat. Chem. Biol. 2013, 9, 43-50.
Wang, L.; Perera, B. G. K.; Hari, S. B.; Bhhatarai, B.; Backes, B. J.; Seeliger, M. A.; Schürer, S. C.; Oakes, S. A.; Papa, F. R.; Maly, D. J. “Divergent allosteric control of the IRE1α endoribonuclease using kinase inhibitors.” Nat. Chem. Biol. 2012, 8, 982-989.