title: Nannocystin A: an Elongation Factor 1 Inhibitor from Myxobacteria with Differential Anti-Cancer Properties.
abstract: Cultivation of myxobacteria of the Nannocystis genus led to the isolation and structure elucidation of a class of novel cyclic lactone inhibitors of elongation factor 1. Whole genome sequence analysis and annotation enabled identification of the putative biosynthetic cluster and synthesis process. In biological assays the compounds displayed anti-fungal and cytotoxic activity. Combined genetic and proteomic approaches identified the eukaryotic translation elongation factor 1α (EF-1α) as the primary target for this compound class. Nannocystin A (1) displayed differential activity across various cancer cell lines and EEF1A1 expression levels appear to be the main differentiating factor. Biochemical and genetic evidence support an overlapping binding site of 1 with the anti-cancer compound didemnin B on EF-1α. This myxobacterial chemotype thus offers an interesting starting point for further investigations of the potential of therapeutics targeting elongation factor 1.
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel (Switzerland).
authors.forename: Philipp
authors.initials: P
authors.lastname: Krastel
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel (Switzerland).
authors.forename: Silvio
authors.initials: S
authors.lastname: Roggo
authors.affiliation: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139 (USA).
authors.forename: Markus
authors.initials: M
authors.lastname: Schirle
authors.affiliation: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139 (USA).
authors.forename: Nathan T
authors.initials: NT
authors.lastname: Ross
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel (Switzerland).
authors.forename: Francesca
authors.initials: F
authors.lastname: Perruccio
authors.affiliation: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139 (USA).
authors.forename: Peter
authors.initials: P
authors.lastname: Aspesi
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel (Switzerland).
authors.forename: Thomas
authors.initials: T
authors.lastname: Aust
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel (Switzerland).
authors.forename: Kathrin
authors.initials: K
authors.lastname: Buntin
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel (Switzerland).
authors.forename: David
authors.initials: D
authors.lastname: Estoppey
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel (Switzerland).
authors.forename: Brigitta
authors.initials: B
authors.lastname: Liechty
authors.affiliation: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139 (USA).
authors.forename: Felipa
authors.initials: F
authors.lastname: Mapa
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel (Switzerland).
authors.forename: Klaus
authors.initials: K
authors.lastname: Memmert
authors.affiliation: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139 (USA).
authors.forename: Howard
authors.initials: H
authors.lastname: Miller
authors.affiliation: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139 (USA).
authors.forename: Xuewen
authors.initials: X
authors.lastname: Pan
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel (Switzerland).
authors.forename: Ralph
authors.initials: R
authors.lastname: Riedl
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel (Switzerland).
authors.forename: Christian
authors.initials: C
authors.lastname: Thibaut
authors.affiliation: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139 (USA).
authors.forename: Jason
authors.initials: J
authors.lastname: Thomas
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel (Switzerland).
authors.forename: Trixie
authors.initials: T
authors.lastname: Wagner
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel (Switzerland).
authors.forename: Eric
authors.initials: E
authors.lastname: Weber
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel (Switzerland).
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Xie
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel (Switzerland).
authors.forename: Esther K
authors.initials: EK
authors.lastname: Schmitt
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel (Switzerland). dominic.hoepfner@novartis.com.
authors.forename: Dominic
authors.initials: D
authors.lastname: Hoepfner
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002176:Candida albicans / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D023281:Genomics / Q000379:methods; D006801:Humans; D047028:Macrocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009231:Myxococcales / Q000502:physiology*; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology*; D020648:Peptide Elongation Factor 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000935:Antifungal Agents; D000970:Antineoplastic Agents; C094814:EEF1A1 protein, human; C503234:EEF1A2 protein, human; D047028:Macrocyclic Compounds; D020648:Peptide Elongation Factor 1; C000607748:nannocystin A
keywords: didemnin B; elongation factor 1α; myxobacteria; nannocystin A; natural products