Professor Jetze J. Tepe, Department of Chemistry Michigan State University Drug Discovery Interdisciplinary Event

1. Natural Product Inspired Scaffolds Design
Jetze J. Tepe, Department of Chemistry
tepe@chemistry.msu.edu
Natural Products New Scaffolds

2. Marine Sponge Metabolites Screening for Biological activity
NF-kB-luc reporter assay screen (HeLa cells)
NF-kB pathway analysis & target identification
Target confirmation in vitro
(purified enzyme assay)
Target validation in vivo
(mouse efficacy models)
Chemical optimization

3. Marine Sponge Metabolites Hymenialdisine
Axinella verrucosa
Pathway: NF-kappaB: Journal of Medicinal Chemistry 2004, 47, 3700
Target: Chk2: Bioorganic & Medicinal Chemistry Letters. 2004, 14, 4319
Chemical optimization: Bioorganic & Medicinal Chemistry 2012, 20, 1475
Application: Protection of normal cells from ionizing radiation
ACS Chemical Biology 2012, 7, 172
Scaffold 1
IC50 8 nM
In collaboration with:
Sandra O’Reilly, Justin McCormick

4. Marine Sponge Metabolites Palau’amine
Pathway: NF-kappaB: Journal of Natural Products 2012, 75, 980-985
Target: Proteasome: Journal of Natural Products 2012, 75, 980-985
Chemical optimization: Organic Letters 2011, 13, 4550-4553
Application: NEW MECHANISM: Multiple myeloma
Angewandte Chemie Int. Ed. 2015 54, 2830-2833.
S3 pocket with
dibromophakellin
S1 pocket with
bortezomib
Common
Ala49Thr
mutation
Covalent 1N
Thr- boronic
ester bond
Our scaffold in
S3 binding
pocket
All other MM
drugs in S1
binding pocket

5. Natural Product Mimics
Pathway: NF-kappaB: Journal of the American Chemical Society 2006,
128, 9137
Target: Proteasome: ACS Chemical Biology, 2013, 8, 578
Chemical optimization: Journal of Medicinal Chemistry, 2013, 56, 5974
Application: Multiple Myeloma
ACS Chemical Biology, 2013, 8, 578
In collaboration with:
Bill Henry, Justin McCormick & Katherine Weilbaecher
End of treatment

6. Natural Product Mimics
Chemical Modification
Mechanism: NEW MECHANISM: Proteasome Assembly
Mycobacterium
Tuberculosis
With Robert Abramovitch