Daniel A. Harki, PhD
Northrop Professor and Margaret Harvey Schering Land Grant Chair for Cancer Research
Contact
Office Address
2-139 CCRB
Minneapolis, MN 55455
United States
Lab Address
2-220 CCRB
Minneapolis, MN 55455
United States
Titles
Northrop Professor
Margaret Harvey Schering Land Grant Chair for Cancer Research
Director of Graduate Studies, Department of Medicinal Chemistry
Affiliated Faculty, Department of Chemistry
Co-Leader, Cellular Mechanisms Program, Masonic Cancer Center (MCC)
Stem Cell Institute
Institute for Molecular Virology
Faculty, PhD Program in Biochemistry, Molecular Biology and Biophysics
Faculty, Masters Program in Stem Cell Biology
Education
PhD, The Pennsylvania State University (Chemistry), 2005
BA, West Virginia University (Biology & Chemistry), 1999
Postdoctoral, California Institute of Technology (Chemistry), 2005-2009
Biography
Summary
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 and antiviral drug development to new tools for modern biochemical research. Our core science is organic chemistry and 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 research groups, we are developing chemical probes and therapeutic molecules targeting the APOBEC3 family of DNA cytosine-to-uracil deaminases. Our approach to new molecule development relies on small molecule and fragment screening using enzyme activity and protein-binding assays, as well as computation- and structure-based designs, to inform our iterative cycles of rational compound design, synthesis, and biochemical/cellular/animal evaluation to optimize the compound.
In collaboration with multiple research groups, we are developing chemical probes and therapeutic molecules targeting the APOBEC3 family of DNA cytosine-to-uracil deaminases. Our approach to new molecule development relies on small molecule and fragment screening using enzyme activity and protein-binding assays, as well as computation- and structure-based designs, to inform our iterative cycles of rational compound design, synthesis, and biochemical/cellular/animal evaluation to optimize the compound.
Chemical Modulation of "Difficult to Drug" Proteins
Many of the most biomedically relevant drug targets are recalcitrant to therapeutic inhibition (they are "difficult to drug"). Our group is interested in developing therapeutic molecules against such targets. Using a variety of ligand- and inhibitor-discovery approaches, we are developing therapeutic molecules to modulate transcription factor signaling and to degrade cellular kinases in which protein depletion is expected to contribute therapeutic benefits beyond inhibition of enzyme activity. Current targets under investigation include the Myc family of transcription factors, Aurora kinase A, and RET kinase.
Many of the most biomedically relevant drug targets are recalcitrant to therapeutic inhibition (they are "difficult to drug"). Our group is interested in developing therapeutic molecules against such targets. Using a variety of ligand- and inhibitor-discovery approaches, we are developing therapeutic molecules to modulate transcription factor signaling and to degrade cellular kinases in which protein depletion is expected to contribute therapeutic benefits beyond inhibition of enzyme activity. Current targets under investigation include the Myc family of transcription factors, Aurora kinase A, and RET kinase.
Antiviral Drug Development
Our research group has a longstanding interest in the development of antiviral nucleosides. We are investigating the potential of 3'-deoxy-3',4'-didehydro ("flat") nucleosides as chain terminating antiviral agents with favorable off-target toxicity profiles. In related work, as part of our recently concluded Midwest AViDD Center, we are developing inhibitors of SARS-CoV-2 main protease (Mpro). These projects have the overarching goal of developing potent, selective, and safe small molecule antiviral therapeutics for future clinical development.
Our research group has a longstanding interest in the development of antiviral nucleosides. We are investigating the potential of 3'-deoxy-3',4'-didehydro ("flat") nucleosides as chain terminating antiviral agents with favorable off-target toxicity profiles. In related work, as part of our recently concluded Midwest AViDD Center, we are developing inhibitors of SARS-CoV-2 main protease (Mpro). These projects have the overarching goal of developing potent, selective, and safe small molecule antiviral therapeutics for future clinical development.
Awards & Recognition
- Fellow of the Royal Society of Chemistry (FRSC), 2025
- Professor of the Semester, UMN, College of Pharmacy, PharmD Class of 2028, 2025
- Margaret Harvey Schering Land Grant Chair for Cancer Research, UMN, 2024
- American Association for Cancer Research – Bayer Innovation and Discovery Grant, 2021
- 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
Publications
- Anderson JJ and Harki DA. Identification of a novel allosteric binding site on the catalytic domain of NF-κB inducing kinase (NIK). RSC Med. Chem. 2025, 16, 1681-1685.
- Tang J, Moorthy R, Hirsch LE, Demir Ö, Baker ZD, Naumann JA, Jones KFM, Grillo MJ, Haefner ES, Shi K, Levy MJ, Gupta HB, Aihara H, Harris RS, Amaro RE, Levinson NM, and Harki DA. Targeting N-Myc in neuroblastoma with selective Aurora kinase A degraders. Cell Chem. Biol. 2025, 32, 352-362.
- Wyllie MK, Morris CK, Moeller NH, Schares HAM, Moorthy R, Belica CA, Grillo MJ, Demir Ö, Ayoub AM, Carpenter MA, Aihara H, Harris RS, Amaro RE, and Harki DA. The impact of sugar conformation on the single-stranded DNA selectivity of APOBEC3A and APOBEC3B enzymes. ACS Chem. Biol. 2025, 20, 117-127.
- Kennelly SA†, Sawyer JM†, Payne AF, Ciota TA, and Harki DA. Development of 3ʹ-deoxy-3ʹ,4ʹ-didehydro-nucleoside prodrug inhibitors of West Nile and Zika viruses. ACS Med. Chem. Lett. 2024, 15, 1334-1339.
- Anderson JJ, Grillo MJ, and Harki DA. Development of allosteric NIK ligands from fragment-based NMR screening. ACS Med. Chem. Lett. 2023, 14, 1815-1820.
- Passow KT and Harki DA. 4-Isocyanoindole-2ʹ-deoxyribonucleoside (4ICIN): An isomorphic indole nucleoside suitable for inverse electron demand Diels-Alder reactions. Tetrahedron Lett. 2023, 132, 154807.