title: SU9516 Increases α7β1 Integrin and Ameliorates Disease Progression in the mdx Mouse Model of Duchenne Muscular Dystrophy.
abstract: Duchenne muscular dystrophy (DMD) is a fatal muscle disease caused by mutations in the dystrophin gene, resulting in a complete loss of the dystrophin protein. Dystrophin is a critical component of the dystrophin glycoprotein complex (DGC), which links laminin in the extracellular matrix to the actin cytoskeleton within myofibers and provides resistance to shear stresses during muscle activity. Loss of dystrophin in DMD patients results in a fragile sarcolemma prone to contraction-induced muscle damage. The α7β1 integrin is a laminin receptor protein complex in skeletal and cardiac muscle and a major modifier of disease progression in DMD. In a muscle cell-based screen for α7 integrin transcriptional enhancers, we identified a small molecule, SU9516, that promoted increased α7β1 integrin expression. Here we show that SU9516 leads to increased α7B integrin in murine C2C12 and human DMD patient myogenic cell lines. Oral administration of SU9516 in the mdx mouse model of DMD increased α7β1 integrin in skeletal muscle, ameliorated pathology, and improved muscle function. We show that these improvements are mediated through SU9516 inhibitory actions on the p65-NF-κB pro-inflammatory and Ste20-related proline alanine rich kinase (SPAK)/OSR1 signaling pathways. This study identifies a first in-class α7 integrin-enhancing small-molecule compound with potential for the treatment of DMD.
authors.affiliation: Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557, USA.
authors.forename: Apurva
authors.initials: A
authors.lastname: Sarathy
authors.affiliation: Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557, USA.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Wuebbles
authors.affiliation: Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557, USA.
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Fontelonga
authors.affiliation: Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557, USA.
authors.forename: Ashley R
authors.initials: AR
authors.lastname: Tarchione
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD 20850, USA.
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Mathews Griner
authors.affiliation: Department of Physiology, University of Nevada School of Medicine, Reno, NV 89557, USA.
authors.forename: Dante J
authors.initials: DJ
authors.lastname: Heredia
authors.affiliation: Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557, USA.
authors.forename: Andreia M
authors.initials: AM
authors.lastname: Nunes
authors.affiliation: Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557, USA.
authors.forename: Suzann
authors.initials: S
authors.lastname: Duan
authors.affiliation: Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Brewer
authors.affiliation: Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557, USA.
authors.forename: Tyler
authors.initials: T
authors.lastname: Van Ry
authors.affiliation: Department of Physiology, University of Nevada School of Medicine, Reno, NV 89557, USA.
authors.forename: Grant W
authors.initials: GW
authors.lastname: Hennig
authors.affiliation: Department of Physiology, University of Nevada School of Medicine, Reno, NV 89557, USA.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Gould
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD 20850, USA.
authors.forename: Andrés E
authors.initials: AE
authors.lastname: Dulcey
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD 20850, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Wang
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD 20850, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD 20850, USA.
authors.forename: Catherine Z
authors.initials: CZ
authors.lastname: Chen
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD 20850, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Hu
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD 20850, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD 20850, USA.
authors.forename: Noel
authors.initials: N
authors.lastname: Southall
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD 20850, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Ferrer
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD 20850, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Marugan
authors.affiliation: Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557, USA. Electronic address: dburkin@medicine.nevada.edu.
authors.forename: Dean J
authors.initials: DJ
authors.lastname: Burkin
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005355:Fibrosis; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D016023:Integrins / Q000819:agonists / Q000378:metabolism*; D051379:Mice; D018101:Mice, Inbred mdx; D008954:Models, Biological; D024510:Muscle Development / Q000187:drug effects; D053580:Muscle Strength; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007093:Imidazoles; D007211:Indoles; D016023:Integrins; D016328:NF-kappa B; C433985:SU 9516; C000621978:integrin alpha 7 beta 1, mouse; C486407:Stk39 protein, mouse; C534421:OXSR1 protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: Duchenne muscular dystrophy; small molecule therapy; α7β1