Design, synthesis, and evaluation of cystargolide-based β-lactones as potent proteasome inhibitors
- Eur J Med Chem. 2018 Sep 5:157:962-977. doi: 10.1016/j.ejmech.2018.08.052.
- 1. Department of Chemistry, New Mexico Institute of Mining and Technology, Socorro, NM 87801, USA.
- 2. Department of Chemistry, New Mexico Institute of Mining and Technology, Socorro, NM 87801, USA; Department of Biology, New Mexico Institute of Mining and Technology, Socorro, NM 87801, USA.
- 3. Center for Integrated Protein Science at the Department Chemie, Technische Universitat München, Lichtenbergstraße 4, 85748 Garching, Germany.
- 4. Department of Biology, New Mexico Institute of Mining and Technology, Socorro, NM 87801, USA.
- 5. Department of Chemistry, New Mexico Institute of Mining and Technology, Socorro, NM 87801, USA. Electronic address: [email protected].
The peptidic β-lactone Proteasome inhibitors (PIs) cystargolides A and B were used to conduct structure-activity relationship (SAR) studies in order to assess their Anticancer potential. A total of 24 different analogs were designed, synthesized and evaluated for Proteasome inhibition, for cytotoxicity towards several Cancer cell lines, and for their ability to enter intact cells. X-ray crystallographic analysis and subunit selectivity was used to determine the specific subunit binding associated with the structural modification of the β-lactone (P1), peptidic core, (Px and Py), and end-cap (Pz) of our scaffold. The cystargolide derivative 5k, structurally unique at both Py and P1, exhibited the most promising inhibitory activity for the β5 subunit of human proteasomes (IC50 = 3.1 nM) and significant cytotoxicity towards MCF-7 (IC50 = 416 nM), MDA-MB-231 (IC50 = 74 nM) and RPMI 8226 (IC50 = 41 nM) Cancer cell lines. Cellular infiltration assays revealed that minor structural modifications have significant effects on the ability of our PIs to inhibit intracellular proteasomes, and we identified 5k as a promising candidate for continued therapeutic studies. Our novel drug lead 5k is a more potent Proteasome Inhibitor than carfilzomib with mid-to-low nanomolar IC50 measurements and it is cytotoxic against multiple Cancer cell lines at levels approaching those of carfilzomib.