2. Academic Validation
  3. Design, synthesis, and evaluation of cystargolide-based β-lactones as potent proteasome inhibitors

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.
Doleshwar Niroula 1,  Liam P Hallada 2,  Camille Le Chapelain 3,  Susantha K Ganegamage 1,  Devon Dotson 4,  Snezna Rogelj 4,  Michael Groll 3,  Rodolfo Tello-Aburto 5
Affiliations

Affiliations

  • 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: rodolfo.tello-aburto@nmt.edu.
PMID: 30165344 DOI: 10.1016/j.ejmech.2018.08.052
Abstract

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.

Keywords

Beta-lactones; Cystargolides; Cytotoxicity; Proteasome inhibitors; Structure-activity relationship.

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