title: AMF-26, a novel inhibitor of the Golgi system, targeting ADP-ribosylation factor 1 (Arf1) with potential for cancer therapy.
abstract: ADP-ribosylation factor 1 (Arf1) plays a major role in mediating vesicular transport. Brefeldin A (BFA), a known inhibitor of the Arf1-guanine nucleotide exchange factor (GEF) interaction, is highly cytotoxic. Therefore, interaction of Arf1 with ArfGEF is an attractive target for cancer treatment. However, BFA and its derivatives have not progressed beyond the pre-clinical stage of drug development because of their poor bioavailability. Here, we aimed to identify novel inhibitors of the Arf1-ArfGEF interaction that display potent antitumor activity in vivo but with a chemical structure distinct from that of BFA. We exploited a panel of 39 cell lines (termed JFCR39) coupled with a drug sensitivity data base and COMPARE algorithm, resulting in the identification of a possible novel Arf1-ArfGEF inhibitor AMF-26, which differed structurally from BFA. By using a pulldown assay with GGA3-conjugated beads, we demonstrated that AMF-26 inhibited Arf1 activation. Subsequently, AMF-26 induced Golgi disruption, apoptosis, and cell growth inhibition. Computer modeling/molecular dynamics (MD) simulation suggested that AMF-26 bound to the contact surface of the Arf1-Sec7 domain where BFA bound. AMF-26 affected membrane traffic, including the cis-Golgi and trans-Golgi networks, and the endosomal systems. Furthermore, using AMF-26 and its derivatives, we demonstrated that there was a significant correlation between cell growth inhibition and Golgi disruption. In addition, orally administrated AMF-26 (83 mg/kg of body weight; 5 days) induced complete regression of human breast cancer BSY-1 xenografts in vivo, suggesting that AMF-26 is a novel anticancer drug candidate that inhibits the Golgi system, targeting Arf1 activation.
authors.affiliation: Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Ohashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Iijima
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Yamaotsu
authors.forename: Kanami
authors.initials: K
authors.lastname: Yamazaki
authors.forename: Shigeo
authors.initials: S
authors.lastname: Sato
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Okamura
authors.forename: Kenji
authors.initials: K
authors.lastname: Sugimoto
authors.forename: Shingo
authors.initials: S
authors.lastname: Dan
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hirono
authors.forename: Takao
authors.initials: T
authors.lastname: Yamori
mesh_terms: D020823:ADP-Ribosylation Factor 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000465:Algorithms; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003198:Computer Simulation; D016208:Databases, Factual; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D021601:trans-Golgi Network / Q000201:enzymology*
chemical_list: D004791:Enzyme Inhibitors; D020823:ADP-Ribosylation Factor 1