Meayamycin inhibits pre-messenger RNA splicing and exhibits picomolar activity against multidrug-resistant cells.
FR901464 is a potent antitumor natural product that binds to the splicing factor 3b complex and inhibits pre-mRNA splicing. Its analogue, meayamycin, is two orders of magnitude more potent as an antiproliferative agent against human breast cancer MCF-7 cells. Here, we report the picomolar antiproliferative activity of meayamycin against various cancer cell lines and multidrug-resistant cells. Time-dependence studies implied that meayamycin may form a covalent bond with its target protein(s). Meayamycin inhibited pre-mRNA splicing in HEK-293 cells but not alternative splicing in a neuronal system. Meayamycin exhibited specificity toward human lung cancer cells compared with nontumorigenic human lung fibroblasts and retained picomolar growth-inhibitory activity against multidrug-resistant cells. These data suggest that meayamycin is a useful chemical probe to study pre-mRNA splicing in live cells and is a promising lead as an anticancer agent.
Albert
Brian J
BJ
Departments of 1Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
McPherson
Peter A
PA
O'Brien
Kristine
K
Czaicki
Nancy L
NL
Destefino
Vincent
V
Osman
Sami
S
Li
Miaosheng
M
Day
Billy W
BW
Grabowski
Paula J
PJ
Moore
Melissa J
MJ
Vogt
Andreas
A
Koide
Kazunori
K
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm; D004852:Epoxy Compounds / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011714:Pyrans / Q000737:chemistry / Q000494:pharmacology*; D012322:RNA Precursors / Q000378:metabolism*; D012326:RNA Splicing / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism*; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology
D000970:Antineoplastic Agents; D004852:Epoxy Compounds; C104486:FR 901464; D011714:Pyrans; D012322:RNA Precursors; D012333:RNA, Messenger; D013141:Spiro Compounds; C546442:meayamycin