Daniel A. Harki, PhD
PhD, The Pennsylvania State University (Chemistry), 2005
BA, West Virginia University (Biology & Chemistry), 1999
Postdoctoral, California Institute of Technology (Chemistry), 2005-2009
Research in the Harki laboratory focuses on the design, synthesis and biological characterization of novel small molecules, peptides, and oligonucleotides that influence cellular function. Applications for these molecules range from anticancer drug discovery to new tools for modern biotechnology research. Our core science is organic chemistry. However, we use techniques of modern biochemistry, biophysics, and cellular/molecular biology to evaluate the biological activities of the compounds we synthesize.
Development of APOBEC3 Chemical Probes
In collaboration with multiple groups at the University of Minnesota and external, we are developing the first-in-class chemical probes of the APOBEC3 family of DNA cytosine-to-uracil deaminases. Our approach to chemical probe discovery relies on high-throughput small molecule and fragment screening, as well as computation- and structure-based designs, to inform our iterative cycles of rational compound design, synthesis, and biochemical/cellular evaluation.
Chemical Modulation of Transcription Factor Signaling
Aberrant transcription factor (TF) signaling drives the progression of numerous diseases and represents a formidable challenge for the development of chemical probes. We are developing small molecule and nucleic acid-based chemical probes of multiple TFs, including NF-kB and androgen receptor. We are particularly focused on covalent inhibitors of TF signaling networks with a strong interest in natural product-based analogues. Additionally, our group has extensive experience synthesizing non-natural nucleosides and oligonucleotides, which are useful for developing TF-targeted probes.
Awards & Recognition
- Northrop Professorship, University of Minnesota, 2020
- Inductee, Rho Chi Pharmacy Honor Society, Mu Chapter, 2016
- Professor of the Semester, University of Minnesota, College of Pharmacy, Class of 2013 - Duluth, Fall 2013
- V Foundation V Scholar, V Foundation for Cancer Research, 2012
- California Tobacco-Related Disease Research Program, Postdoctoral Fellowship, 2007-09
- Friedreich's Ataxia Research Alliance, Postdoctoral Fellowship, 2006-07
- American Heart Association, Predoctoral Fellowship, 2002-05
- Phi Beta Kappa, Alpha of West Virginia, West Virginia University, 1999
- Grillo MJ, Jones KFM, Carpenter MA, Harris RS, Harki DA. The current toolbox for APOBEC drug discovery. Trends Pharmacol Sci. 2022 May;43(5):362-377. doi: 10.1016/j.tips.2022.02.007. PMID: 35272863; PMCID: PMC9018551.
- Frank, D., Moorthy, R., Widen, J. C., Khandanpour, C., Harki, D. A., Klempnauer, K.-H., Ghani, L. A., Yusenko, M. V., & Doerner, W. (2022). A synthetic covalent ligand of the C/EBP beta transactivation domain inhibits acute myeloid leukemia cells. CANCER LETTERS, 530, 170-180. doi: 10.1016/j.canlet.2022.01.024
- Divakaran A, Scholtz CR, Zahid H, Lin W, Griffith EC, Lee RE, Chen T, Harki DA, Pomerantz WCK. Development of an N-Terminal BRD4 Bromodomain-Targeted Degrader. ACS Med Chem Lett. 2022 Sep 29;13(10):1621-1627. doi: 10.1021/acsmedchemlett.2c00300. PMID: 36262390; PMCID: PMC9575167.
- Cui H, Divakaran A, Hoell ZJ, Ellingson MO, Scholtz CR, Zahid H, Johnson JA, Griffith EC, Gee CT, Lee AL, Khanal S, Shi K, Aihara H, Shah VH, Lee RE, Harki DA, Pomerantz WCK. A Structure-based Design Approach for Generating High Affinity BRD4 D1-Selective Chemical Probes. J Med Chem. 2022 Feb 10;65(3):2342-2360. doi: 10.1021/acs.jmedchem.1c01779. Epub 2022 Jan 10. PMID: 35007061; PMCID: PMC9683399.
- Kennelly SA, Moorthy R, Otero RS, Harki DA. Expanding Catch and Release DNA Decoy (CRDD) Technology with Pyrimidine Mimics. Chemistry. 2022 Oct 18;28(58):e202201355. doi: 10.1002/chem.202201355. Epub 2022 Aug 25. PMID: 35849314; PMCID: PMC9588621.
- Moghadasi, S. A., Esler, M. A., Otsuka, Y., Becker, J. T., Moraes, S. N., Anderson, C. B., Chamakuri, S., Belica, C., Wick, C., Harki, D. A., Young, D. W., Scampavia, L., Spicer, T. P., Shi, K., Aihara, H.,Brown, W. L., & Harris, R. S. (2022). Gain-of-Signal Assays for Probing Inhibition of SARS-CoV-2 M-pro/3CL(pro) in Living Cells. MBIO, 13(3). doi: 10.1128/mbio.00784-22
- Moeller, N. H., Passow, K. T., Harki, D. A., & Aihara, H. (2022). SARS-CoV-2 nsp14 Exoribonuclease Removes the Natural Antiviral 3 '-Deoxy-3 ',4 '-didehydro-cytidine Nucleotide from RNA. VIRUSES-BASEL, 14(8). doi: 10.3390/v1408179