DcpS as a therapeutic target for spinal muscular atrophy.
Spinal muscular atrophy (SMA) is caused by deletion or mutation of both copies of the SMN1 gene, which produces an essential protein known as SMN. The severity of SMA is modified by variable copy number of a second gene,SMN2, which produces an mRNA that is incorrectly spliced with deletion of the last exon. We described previously the discovery of potent C5-substituted quinazolines that increase SMN2 gene expression by 2-fold. Discovery of potent SMN2 promoter inducers relied on a cellular assay without knowledge of the molecular target. Using protein microarray scanning with a radiolabeled C5-substituted quinazoline probe, we identified the scavenger decapping enzyme, DcpS, as a potential binder. We show that the C5-substituted quinazolines potently inhibit DcpS decapping activity and that the potency of inhibition correlates with potency forSMN2 promoter induction. Binding of C5-substituted quinazolines to DcpS holds the enzyme in an open, catalytically incompetent conformation. DcpS is a nuclear shuttling protein that binds and hydrolyzes the m(7)GpppN mRNA cap structure and a modulator of RNA metabolism. Therefore DcpS represents a novel therapeutic target for modulating gene expression by a small molecule.
Singh
Jasbir
J
deCODE chemistry, Inc., 2501 Davey Road, Woodridge, Illinois 60517, USA.
Salcius
Michael
M
Liu
Shin-Wu
SW
Staker
Bart L
BL
Mishra
Rama
R
Thurmond
John
J
Michaud
Gregory
G
Mattoon
Dawn R
DR
Printen
John
J
Christensen
Jeffery
J
Bjornsson
Jon Mar
JM
Pollok
Brian A
BA
Kiledjian
Megerditch
M
Stewart
Lance
L
Jarecki
Jill
J
Gurney
Mark E
ME
D016503:Drug Delivery Systems; D004722:Endoribonucleases / Q000037:antagonists & inhibitors*; D006801:Humans; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy*; D011485:Protein Binding; D011487:Protein Conformation / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology*
D011799:Quinazolines; D004722:Endoribonucleases; C485332:DcpS protein, human