Drug discovery for Duchenne muscular dystrophy via utrophin promoter activation screening.
BACKGROUND
Duchenne muscular dystrophy (DMD) is a devastating muscle wasting disease caused by mutations in dystrophin, a muscle cytoskeletal protein. Utrophin is a homologue of dystrophin that can functionally compensate for its absence when expressed at increased levels in the myofibre, as shown by studies in dystrophin-deficient mice. Utrophin upregulation is therefore a promising therapeutic approach for DMD. The use of a small, drug-like molecule to achieve utrophin upregulation offers obvious advantages in terms of delivery and bioavailability. Furthermore, much of the time and expense involved in the development of a new drug can be eliminated by screening molecules that are already approved for clinical use.


RESULTS
We developed and validated a cell-based, high-throughput screening assay for utrophin promoter activation, and used it to screen the Prestwick Chemical Library of marketed drugs and natural compounds. Initial screening produced 20 hit molecules, 14 of which exhibited dose-dependent activation of the utrophin promoter and were confirmed as hits. Independent validation demonstrated that one of these compounds, nabumetone, is able to upregulate endogenous utrophin mRNA and protein, in C2C12 muscle cells.


CONCLUSIONS
We have developed a cell-based, high-throughput screening utrophin promoter assay. Using this assay, we identified and validated a utrophin promoter-activating drug, nabumetone, for which pharmacokinetics and safety in humans are already well described, and which represents a lead compound for utrophin upregulation as a therapy for DMD.
Department of Physiology and Pennsylvania Muscle Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.
Catherine
C
Moorwood
Olga
O
Lozynska
Neha
N
Suri
Andrew D
AD
Napper
Scott L
SL
Diamond
Tejvir S
TS
Khurana
D001682:Biological Availability; D002460:Cell Line; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000187:drug effects* / Q000235:genetics*; D015203:Reproducibility of Results; D054852:Small Molecule Libraries / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D049411:Utrophin / Q000235:genetics*
D054852:Small Molecule Libraries; D049411:Utrophin