Organic and Medicinal Chemistry

Research in our lab is an interdisciplinary blend of synthetic organic chemistry, medicinal chemistry, and pharmacology.

Total Synthesis of Natural Products
Natural products represent a highly diverse and structurally complex natural library of compounds with remarkable biological and medicinal properties. Our lab develops new chemical methodologies to prepare natural products and natural product mimics with the goal of unraveling new mechanisms of protein regulation and their medicinal implications.

Targeting the Undruggable

Our research focus is on targeting “undruggable proteins” using small molecules to treat cancer and neurodegenerative disorders. We are one of the first to explore the enhancement of proteolytic degradation of classical undruggable proteins, such as c-Myc, a-synuclein, tau, amyloid-b, and others, by activation of the 20S proteasome. As part of this effort, our lab develops new heterocyclic reactions to synthesize complex marine sponge metabolites and their drug-like derivatives. The natural products and their drug-like derivatives are subsequently evaluated and optimized for their clinical significance in vitro, in cell culture and in in vivo disease models.

Representative Publications

1. George, Dare; Tepe, Jetze J. Total Synthesis of Nagelamide W. Journal of Organic Chemistry, 2023, 88, 13, 9306–9312.
2. Savelson, Evan; Tepe, Jetze J. Accessing Highly Oxidized Imidazolidinone Cores via a Curtius Rearrangement: Total Synthesis of Colensolide A. Organic Letters 2023, 25, 3698–3701.
3. Staerz, Sophia S.; Lisabeth, Erika M.; Njomen, Evert; Dexheimer, Thomas S.; Neubig, Richard R.; Tepe, Jetze J. Development of a Cell-Based AlphaLISA Assay for High-Throughput Screening for Small Molecule Proteasome Modulators. ACS Omega, 2023, 8, 15650–15659.
4. Vanecek, Allison, S.; Mojsilovic-Petrovic, Jelena; Kalb, Robert, G.; Tepe, Jetze J. Enhanced Degradation of Mutant C9ORF72-Derived Toxic Dipeptide Repeat Proteins by 20S Proteasome Activation Results in Restoration of Proteostasis and Neuroprotection, ACS Chemical Neuroscience 2023, 14, 1439–1448.
5. Hubbell, Grace E.; Tepe, Jetze J. Rh(III)-catalyzed C-H activation/annulation of benzo- hydroxamates and 2-imidazolones: access to urea-fused-dihydroisoquinolone scaffolds reminiscent of pyrrole-alkaloid natural products, Organic Letters, 2022, 24, 6740–6744.
6. Njomen, Evert; Vanecek, Allison; Lansdell, Theresa A.; et al., Small Molecule 20S Proteasome Enhancer Regulates MYC Protein Stability and Exhibits Antitumor Activity in Multiple Myeloma, Biomedicines 2022, 10, 938.
7. Keel, Katarina L.; and Tepe, Jetze J. Total Synthesis of Nortopsentin D via a Late-Stage Pinacol-like Rearrangement, Organic Letters, 2021, 23, 5368-5372.
8. Fiolek, Taylor J.; Keel, Katarina L. and Tepe, Jetze J. Fluspirilene analogs activate the 20S proteasome and overcome proteasome impairment by intrinsically disorder protein oligomers, ACS Chemical Neuroscience 2021, 12, 1438–1448.

See more (Google Scholars) https://scholar.google.com/citations?user=_DtCKxcAAAAJ&hl=en

Awards and Honors

• William J. Beal Outstanding Faculty Award, MSU, 2022
• MSU Inventor of the Year Award, 2022
• AbbVie Innovation Midwest Award, 2021
• Outstanding Faculty Award, MSU College of Natural Sciences, 2021
• International Myeloma Foundation, Brian D. Novis Award, 2019 & 2013
• Multiple Myeloma Research Foundation Award, 2010 & 2008
• American Cancer Society Research Scholar Award, 2003-2008