个人简介

Pfizer Fellow of the Life Sciences Research Foundation (University of California at San Francisco, 2003-2006) University of California at Berkeley Outstanding Graduate Student Instructor Award (2001) Hilldale Undergraduate Research Fellowship (1996)

研究领域

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.

近期论文

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Andrews, S. S.; Hill, Z. B.; Perera, B. G. K.; Maly, D. J. "Label Transfer Reagents to Probe p38 MAPK Binding Partners." ChemBioChem 2013, 14, 209-216. (DOI: 10.1002/cbic.201200673) Zhang, Z.; Ojo, K. K.; Johnson, S. M.; Larson, E. T.; He, P.; Geiger, J. A.; Castellanos-Gonzalez, A.; White, C. A.; Parsons, M.; Merritt, E. A.; Maly, D. J.; Verlinde, C. L. M. J.; Van Voorhis, W. C.; Fan, E. "Benzoylbenzimidazole-based selective inhibitors targeting Cryptosporidium parvum and Toxoplasma gondii calcium-dependent protein kinase-1." Bioorg. Med. Chem. Lett. 2012, 22, 5264-5267. Larson, E. T.; Ojo, K. K.; Murphy, R. C.; Johnson, S. M.; Zhang, Z.; Kim, J. E.; Leibly, D. J.; Fox, A. M. W.; Reid, M. C.; Dale, E. J.; Perera, B. G. K.; Kim, J.; Hewitt, S. N.; Hol, W. G. J.; Verlinde, C. M. J.; Fan, E.; Van Voorhis, W. C.; Maly, D. J.; Merritt, E. A. "Multiple determinants for selective inhibition of apicomplexan calcium-dependent protein kinase CDPK1." J. Med. Chem. 2012, 55, 2803-2810. (DOI: 10.1021/jm201725v) Hill, Z. B.; Perera, B. G. K.; Andrews, S.; Maly, D. J. "Targeting Diverse Signaling Interaction Sites Allows the Rapid Generation of Bivalent Kinase Inhibitors." ACS Chem. Biol. 2012, 7, 487-495. (DOI: 10.1021/cb200387g) Hari, S. B.; Ranjitkar, P.; Maly, D. J. "Determination of the kinetics and thermodynamics of ligand binding to a specific inactive conformation in protein kinases." Methods Mol. Biol. 2012, 928, 153-159. Ranjitkar, P.; Maly, D. J. "Affinity purification of protein kinases that adopt a specific inactive conformation." Methods Mol. Biol. 2012, 928, 143-151. Goreshnik, I; Brock, A. M.; Maly, D. J. "Biochemical and pharmacological profiling of the pro-survival protein Bcl-xL." Bioorg. Med. Chem. Lett. 2011, 21, 4951-4955. Hill, Z. B.; Perera, B. G. K.; Maly, D. J. "Bivalent inhibitors of the tyrosine kinases ABL and SRC: Molecular determinants of potency and selectivity." Mol. BioSyst. 2011, 7, 447-456. (DOI: 10.1039/c0mb00108b) Krishnamurty, R.; Brock, A. M.; Maly, D. J. "5-AminoIndazoles as general affinity reagents for protein kinases." Bioorg. Med. Chem. Lett. 2011, 21, 550-554. (DOI: 10.1016/j.bmcl.2010.10.069) Murphy, R. C.; Ojo, K. K.; Larson, E. T.; Castellanos-Gonzalez, A.; Perera, B. G. K.; Keyloun, K. R.; Kim, J. E.; Bhandari, J. G.; Muller, N. R.; Verlinde, C. L. M. J.; White, C. A.; Merritt, E. A.; Van Voorhis, W. C.; Maly, D. J. "Discovery of Potent and Selective Inhibitors of Calcium-Dependent Protein Kinase 1 (CDPK1) from C. parvum and T. gondii." ACS Med. Chem. Lett. 2010, 1, 331-335. (DOI: 10.1021/ml100096t) Ojo, K. K.; Larson, E. T.; Keyloun, K. R.; Castaneda, L. J.; DeRocher, A. E.; Inampudi, K. K.; Kim, J. E.; Arakaki, T.; Murphy, R. C.; Zhang, L.; Napuli, A. J.; Maly, D. J.; Verlinde, C. L. M. J.; Buckner, F. S.; Parsons, M.; Hol, W. G. J.; Merritt, E. A.; Van Voorhis W. C. "Toxoplasma gondii calcium-dependent protein kinase 1 is a target for selective kinase inhibitors." Nat. Struct. Mol. Biol. 2010, 17, 602-607. (DOI: 10.1038/nsmb.1818) Gregersen, K. A. D.; Hill, Z. B.; Gadd, J. C.; Fujimoto, B.; Maly, D. J.; Chiu, D. T. "Intracellular Delivery of Bioactive Molecules Using Light-Addressable Nanocapsules." ACS Nano 2010, 4, 7603-7611. (DOI: 10.1021/nn102345f) Krishnamurty, R.; Maly, D. J. "Biochemical Mechanisms of Resistance to Small-Molecule Protein Kinase Inhibitors." ACS Chem. Biol. 2010, 5, 121-138. (DOI: 10.1021/cb9002656) Ranjitkar, P.; Brock, A. M.; Maly, D. J. "Affinity Probes that Target a Specific Inactive Conformation of Protein Kinases." Chem. Biol. 2010, 17, 195-206. (DOI: 10.1016/j.chembiol.2010.01.008) Hill, Z. B.; Perera, B. G. K.; Maly, D. J. "A Chemical Genetic Method for Generating Bivalent Inhibitors of Protein Kinases." J. Am. Chem. Soc. 2009, 131, 6686-6688. (DOI: 10.1021/ja900871y) Seeliger, M. A.; Ranjitkar, P.; Kasap. C.; Shan, Y.; Shaw, D. E.; Shah, N. E.; Kuriyan, J.; Maly, D. J. "Equally Potent Inhibition of c-Src and Abl by Compounds that Recognize Inactive Kinase Conformations." Cancer Res. 2009, 69, 2384-2392. (DOI: 10.1158/0008-5472.CAN-08-3953) Blacken, G. R.; Volný, M.; Diener, M.; Jackson, K. E.; Ranjitkar, P.; Maly, D. J.; Tureček, F. "Reactive Landing of Gas-Phase Ions as a Tool for the Fabrication of Metal Oxide Surfaces for In Situ Phosphopeptide Enrichment." J. Am. Soc. Mass Spectrom. 2009, 20, 915-926. (DOI: 10.1016/j.jasms.2009.01.006). Perera, G.; Maly, D. J. "Design, Synthesis and Characterization of ‘Clickable’ 4-Anilinoquinazoline Kinase Inhibitors." Mol. BioSyst. 2008, 4, 542-550. (DOI: 10.1039/b720014e)