LG186: An inhibitor of GBF1 function that causes Golgi disassembly in human and canine cells.
Brefeldin A-mediated inhibition of ADP ribosylation factor (Arf) GTPases and their guanine nucleotide exchange factors, Arf-GEFs, has been a cornerstone of membrane trafficking research for many years. Brefeldin A (BFA) is relatively non-selective inhibiting at least three targets in human cells, Golgi brefeldin A resistance factor 1 (GBF1), brefeldin A inhibited guanine nucleotide exchange factor 1 (BIG1) and brefeldin A inhibited guanine nucleotide exchange factor 2 (BIG2). Here, we show that the previously described compound Exo2 acts through inhibition of Arf-GEF function, but causes other phenotypic changes that are not GBF1 related. We describe the engineering of Exo2 to produce LG186, a more selective, reversible inhibitor of Arf-GEF function. Using multiple-cell-based assays and GBF1 mutants, our data are most consistent with LG186 acting by selective inhibition of GBF1. Unlike other Arf-GEF and reported GBF1 inhibitors including BFA, Exo2 and Golgicide A, LG186 induces disassembly of the Golgi stack in both human and canine cells.
Boal
Frédéric
F
Cell Biology Laboratories, School of Biochemistry, Medical Sciences Building, University of Bristol, University Walk, Bristol BS8 1TD, UK.
Guetzoyan
Lucie
L
Sessions
Richard B
RB
Zeghouf
Mahel
M
Spooner
Robert A
RA
Lord
J Michael
JM
Cherfils
Jacqueline
J
Clarkson
Guy J
GJ
Roberts
Lynne M
LM
Stephens
David J
DJ
D020823:ADP-Ribosylation Factor 1 / Q000037:antagonists & inhibitors; D000595:Amino Acid Sequence; D000818:Animals; D001547:Benzaldehydes / Q000494:pharmacology; D020126:Brefeldin A / Q000494:pharmacology; D002460:Cell Line; D004285:Dogs; D006056:Golgi Apparatus / Q000187:drug effects* / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis / Q000494:pharmacology*; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology
C495416:4-hydroxy-3-methoxy-(5,6,7,8-tetrahydro(1)benzothieno(2,3-d)pyrimidin-4-yl)hydrazone benzaldehyde; D001547:Benzaldehydes; C120445:GBF1 protein, human; D020662:Guanine Nucleotide Exchange Factors; D006575:Heterocyclic Compounds, 3-Ring; D006835:Hydrazones; C556515:LG 186; D011725:Pyridines; D011743:Pyrimidines; D011804:Quinolines; C539165:golgicide A; D020126:Brefeldin A; D020823:ADP-Ribosylation Factor 1