David E. Heppner
PhD
Jere Solo Assistant Professor of Medicinal Chemistry
Research Interests
Chemical biology, medicinal chemistry, structure-guided drug design, protein biochemistry, structural biology, cancer biology, protein kinases, allosteric inhibitors, targeted protein degradation, bioinorganic chemistry, redox biology, and biorthogonal chemistry.
Education
- Postdoctoral Research Fellow, Dana-Farber Cancer Institute and Havard Medical School, Boston, MA, 2017-2020
- NIH Postdoctoral Fellow, Larner College of Medicine at the University of Vermont, Burlington, VT, 2014-2017
- PhD, Stanford University, Stanford, CA, 2014
- BS Chem., Summa Cum Laude, University of Minnesota, MN, 2007
Awards and Honors
- NIH Early Career Reviewer
- CTSI BTC K Scholar, 2022
- Co-chair of Gordon Research Seminar on NADPH Oxidase Enzymes, 2018
- Young Investigator Award, SFRBM, 2016
- Ruth L. Kirschstein NRSA Postdoctoral Fellowship (F32), NIH, 2016
- Beckman Scholar, 2006
Specializations
- Protein biochemistry, enzymology, and molecular biology
- Drug discovery, pharmacology, and medicinal chemistry
- Bioinorganic chemistry and redox biology
- Biophysical techniques and spectroscopy
- Targeted protein degradation
- Structural biology
Research Summary
The Heppner lab studies molecules, proteins, and cells to develop innovative solutions to persistent challenges in human health. We apply an integrative approach through a combination of medicinal chemistry, biochemistry, cellular and molecular biology, biophysics, and structural biology to discover and design novel therapeutics and molecular tools for biological applications. Our research is equally directed to understand protein structural and mechanistic essentials that control biochemical processes important in cancer biology and other diseases. Current areas of interest include:
- Discovery and design of first-in-class small molecule inhibitors as targeted therapies in cancer and other diseases.
- Structural and functional understanding of post-translational modifications at protein cysteine residues.
- Pharmacology and structural biology of metalloproteins and redox enzymes.
Selected Recent Publications
Google Scholar: Link
- T.S. Beyett, J.K. Rana, I.K. Schaeffner, D.E. Heppner, M.J. Eck. Structural analysis of the macrocyclic inhibitor BI-4020 binding to EGFR kinase. bioRxiv 2022 https://doi.org/10.1101/2022.08.27.505540
- D.E. Heppner et al., Structural Basis for Inhibition of Mutant EGFR with Lazertinib (YH25448). ACS Medicinal Chemistry Letters 2022 https://pubs.acs.org/doi/full/10.1021/acsmedchemlett.2c00213
- B.C. Ogboo, U.V. Grabovyy, A. Maini, S. Scouten, A. van der Vliet, A. Mattevi, and David E. Heppner. “Architecture of the NADPH Oxidase Family of Enzymes.” Redox Biology 2022 https://doi.org/10.1016/j.redox.2022.102298
- F. Wittlinger, D.E. Heppner et al., Design of a “Two-in-One” Mutant-Selective Epidermal Growth Factor Receptor Inhibitor That Spans the Orthosteric and Allosteric Sites. Journal of Medicinal Chemistry 2022 https://doi.org/10.1021/acs.jmedchem.1c00848
- D.E. Heppner and M.J. Eck. A structural perspective on targeting the RTK/Ras/MAP kinase pathway in cancer. Protein Science. 2021. https://doi.org/10.1002/pro.4125
- D.E. Heppner, Structural Insights Into Redox-active Cysteine Residues of the Src Family Kinases, Redox Biology. 2021. https://doi.org/10.1016/j.redox.2021.101934
- D.E. Heppner et al., Structural Basis for EGFR Inhibition by Trisubstituted Imidazole Inhibitors. Journal of Medicinal Chemistry. 2020. https://doi.org/10.1021/acs.jmedchem.0c00200
- D.J.H. De Clercq, D.E. Heppner et al., Discovery and Optimization of Dibenzodiazepinones as Allosteric Mutant-Selective EGFR Inhibitors. ACS Medicinal Chemistry Letters. 2019. https://doi.org/10.1021/acsmedchemlett.9b00381
- D.E Heppner, C.M. Dustin, C. Liao, et al., Direct Cysteine Sulfenylation Drives Activation of the Src Kinase. Nature Communications. 2018. https://doi.org/10.1038/s41467-018-06790-1
- D.E. Heppner et al., Cysteine perthiosulfenic acid (Cys-SSOH): A novel intermediate in thiol-based redox signaling. Redox Biology. 2018. https://doi.org/10.1016/j.redox.2017.10.006
- D.E. Heppner, Y.M.W. Janssen-Heininger, and A. van der Vliet. The role of sulfenic acids in cellular redox siganling: Reconciling chemical kinetics and molecular detection strategies. Archives of Biochemistry and Biophysics. 2017. https://doi.org/10.1016/j.abb.2017.01.008
- D.E. Heppner et al., The NADPH oxidases DUOX1 and NOX2 play distinct roles in redox regulation of epidermal growth factor receptor signaling. Journal of Biological Chemistry. 2016. https://doi:10.1074/jbc.M116.749028
- D.E. Heppner and A. van der Vliet. Redox-dependent regulation of epidermal growth factor receptor signaling. Redox Biology. 2016. https://doi.org/10.1016/j.redox.2015.12.002
- D.E. Heppner et al., Mechanism of the reduction of the native intermediate in the multicopper oxidases: Insights into rapid intramolecular electron transfer in turnover. Journal of the American Chemical Society. 2014. https://doi.org/10.1021/ja509150j
- D.E. Heppner et al., Molecular origin of rapid versus slow intramolecular electron transfer in the catalytic mechanism of the multicopper oxidases. Journal of the American Chemical Society. 2013. https://doi.org/10.1021/ja4064525