Skip Navigation



Human Molecular Genetics Advance Access published online on June 8, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi205
This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
14/14/2003    most recent
ddi205v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Jarecki, J.
Right arrow Articles by Pollok, B. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Jarecki, J.
Right arrow Articles by Pollok, B. A.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2005. Published by Oxford University Press. All rights reserved
Received March 21, 2005
Revised May 12, 2005
Accepted May 24, 2005

Article

Diverse small-molecule modulators of SMN expression found by high-throughput compound screening: Early leads towards a therapeutic for Spinal Muscular Atrophy

Jill Jarecki 1*, Xiaocun Chen 2, Alexandra Bernardino 2, Daniel D. Coovert 3, Michael Whitney 2, Arthur Burghes 4, Jeffrey Stack 2, and Brian A. Pollok 2

1 Vertex Pharmaceuticals, Inc. 11010 Torreyana Road, San Diego, CA 92121; Families of SMA, Libertyville, IL 60048
2 Vertex Pharmaceuticals, Inc. 11010 Torreyana Road, San Diego, CA 92121
3 Department of Molecular and Cellular Biology, Ohio State University, Columbus, OH 43210
4 Department of Molecular Genetics, College of Biological Sciences, Ohio State University, Columbus, OH 43210; Department of Neurology, College of Medicine, Ohio State University, Columbus, OH 43210; Department of Molecular and Cellular Biology, Ohio State University, Columbus, OH 43210

* To whom correspondence should be addressed.
Jill Jarecki, E-mail: jill{at}fsma.org


  Abstract

We have exploited the existence of a second copy of the human SMN gene (SMN2) to develop a high throughput screening (HTS) strategy to identify potential small molecule therapeutics for the genetic disease Spinal Muscular Atrophy (SMA), which is caused by the loss of the SMN1 gene. Our screening process was designed to identify synthetic compounds that increase the total amount of full-length SMN messenger RNA and protein arising from the SMN2 gene, thereby suppressing the deleterious effects of losing SMN1. A cell-based bioassay was generated that detects SMN2 promoter activity, on which greater than 550,000 compounds were tested. This resulted in the identification of 17 distinct compounds with confirmed biological activity on the cellular primary assay, belonging to nine different structural families. Six of the nine scaffolds were chosen on the basis of their drug-like features to be tested for their ability to modulate SMN gene expression in SMA patient-derived fibroblasts. Five of the six compound classes altered SMN mRNA levels or mRNA splicing patterns in SMA patient-derived fibroblasts. Two of the compound classes, a quinazoline compound series and an indole compound, also increased SMN protein levels and nuclear gem/Cajal Body numbers in patient-derived cells. In addition, these two distinct scaffolds showed additive effects when used in combination, suggesting that they may act on different molecular targets. The work described here has provided the foundation for a successful medicinal chemistry effort to further advance these compounds as potential small molecule therapeutics for SMA.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Hum Mol GenetHome page
M. E.R. Butchbach, J. Singh, M. Thorsteinsdottir, L. Saieva, E. Slominski, J. Thurmond, T. Andresson, J. Zhang, J. D. Edwards, L. R. Simard, et al.
Effects of 2,4-diaminoquinazoline derivatives on SMN expression and phenotype in a mouse model for spinal muscular atrophy
Hum. Mol. Genet., November 25, 2009; (2009) ddp510v2.
[Abstract] [Full Text] [PDF]

Home page
 Sci Transl MedHome page
M. L. Hastings, J. Berniac, Y. H. Liu, P. Abato, F. M. Jodelka, L. Barthel, S. Kumar, C. Dudley, M. Nelson, K. Larson, et al.
Tetracyclines That Promote SMN2 Exon 7 Splicing as Therapeutics for Spinal Muscular Atrophy
Science Translational Medicine, November 4, 2009; 1(5): 5ra12 - 5ra12.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
L. Garbes, M. Riessland, I. Holker, R. Heller, J. Hauke, C. Trankle, R. Coras, I. Blumcke, E. Hahnen, and B. Wirth
LBH589 induces up to 10-fold SMN protein levels by several independent mechanisms and is effective even in cells from SMA patients non-responsive to valproate
Hum. Mol. Genet., October 1, 2009; 18(19): 3645 - 3658.
[Abstract] [Full Text] [PDF]

Home page
 NeurologyHome page
N. thi Man, E. Humphrey, L. T. Lam, H. R. Fuller, T. A. Lynch, C. A. Sewry, P. R. Goodwin, A. E. MacKenzie, and G. E. Morris
A two-site ELISA can quantify upregulation of SMN protein by drugs for spinal muscular atrophy
Neurology, November 25, 2008; 71(22): 1757 - 1763.
[Abstract] [Full Text] [PDF]

Home page
 J. Med. Genet.Home page
C Angelozzi, F Borgo, F D Tiziano, A Martella, G Neri, and C Brahe
Salbutamol increases SMN mRNA and protein levels in spinal muscular atrophy cells
J. Med. Genet., January 1, 2008; 45(1): 29 - 31.
[Abstract] [Full Text] [PDF]

Home page
 J Child NeurolHome page
K. J. Swoboda, J. T. Kissel, T. O. Crawford, M. B. Bromberg, G. Acsadi, G. D'Anjou, K. J. Krosschell, S. P. Reyna, M. K. Schroth, C. B. Scott, et al.
Perspectives on Clinical Trials in Spinal Muscular Atrophy
J Child Neurol, August 1, 2007; 22(8): 957 - 966.
[Abstract] [PDF]

Home page
 Nucleic Acids ResHome page
J. P. Orengo, D. Bundman, and T. A. Cooper
A bichromatic fluorescent reporter for cell-based screens of alternative splicing
Nucleic Acids Res., December 2, 2006; 34(22): e148 - e148.
[Abstract] [Full Text] [PDF]

Home page
 NeurologyHome page
C. J. Sumner, S. J. Kolb, G. G. Harmison, N. O. Jeffries, K. Schadt, R. S. Finkel, G. Dreyfuss, and K. H. Fischbeck
SMN mRNA and protein levels in peripheral blood: Biomarkers for SMA clinical trials
Neurology, April 11, 2006; 66(7): 1067 - 1073.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.