title: Actinopolysporins A-C and tubercidin as a Pdcd4 stabilizer from the halophilic actinomycete Actinopolyspora erythraea YIM 90600.
abstract: Our current natural product program utilizes new actinomycetes originating from unexplored and underexplored ecological niches, employing cytotoxicity against a selected panel of cancer cell lines as the preliminary screen to identify hit strains for natural product dereplication, followed by mechanism-based assays of the purified natural products to discover potential anticancer drug leads. Three new linear polyketides, actinopolysporins A (1), B (2), and C (3), along with the known antineoplastic antibiotic tubercidin (4), were isolated from the halophilic actinomycete Actinopolyspora erythraea YIM 90600, and the structures of the new compounds were elucidated on the basis of spectroscopic data interpretation. All four compounds were assayed for their ability to stabilize the tumor suppressor programmed cell death protein 4 (Pdcd4), which is known to antagonize critical events in oncogenic pathways. Only 4 significantly inhibited proteasomal degradation of a model Pdcd4-luciferase fusion protein, with an IC50 of 0.88±0.09 μM, unveiling a novel biological activity for this well-studied natural product.
authors.affiliation: Yunnan Institute of Microbiology, Yunnan University, Kunming, Yunnan 650091, People's Republic of China.
authors.forename: Li-Xing
authors.initials: LX
authors.lastname: Zhao
authors.forename: Sheng-Xiong
authors.initials: SX
authors.lastname: Huang
authors.forename: Shu-Kun
authors.initials: SK
authors.lastname: Tang
authors.forename: Cheng-Lin
authors.initials: CL
authors.lastname: Jiang
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Duan
authors.forename: John A
authors.initials: JA
authors.lastname: Beutler
authors.forename: Curtis J
authors.initials: CJ
authors.lastname: Henrich
authors.forename: James B
authors.initials: JB
authors.lastname: McMahon
authors.forename: Tobias
authors.initials: T
authors.lastname: Schmid
authors.forename: Johanna S
authors.initials: JS
authors.lastname: Blees
authors.forename: Nancy H
authors.initials: NH
authors.lastname: Colburn
authors.forename: Scott R
authors.initials: SR
authors.lastname: Rajski
authors.forename: Ben
authors.initials: B
authors.lastname: Shen
mesh_terms: D039903:Actinobacteria / Q000302:isolation & purification*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects; D001688:Biological Products / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007659:Ketones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D015394:Molecular Structure; D061065:Polyketides; D016601:RNA-Binding Proteins / Q000187:drug effects; D014372:Tubercidin / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D001688:Biological Products; D007659:Ketones; C114487:PDCD4 protein, human; D061065:Polyketides; D016601:RNA-Binding Proteins; C562187:actinopolysporin A; C562188:actinopolysporin B; C562189:actinopolysporin C; D014372:Tubercidin