Connect with Families of SMA:

Families of SMA began the Quinazoline (DcpS inhibitor project) in 2000 with Aurora Bioscience / Vertex Pharmaceuticals by performing drug screens for SMA. 

deCODE Chemistry began working on behalf of FSMA to create a new drug for the treatment of SMA in 2003, starting from the lead compounds discovered in the drug screens at Aurora / Vertex.

A similar project was funded at Aurora at the same time by the Cystic Fibrosis Foundation.  Vertex recently filed a New Drug Application with the FDA as a result of that work.  Please click here to read about the October 2011 NDA filing. 

The overall goal of the project is to increase the amount of functional SMN protein produced from a second almost identical gene called SMN2, which remains intact in SMA patients.  Normally the SMN2 gene makes very little functional protein.  However, boosting the amount produced from the intact SMN2 gene is a viable therapeutic strategy for SMA. This strategy is described below.

1. Most people have SMN1 and SMN2 genes. Full-length SMN protein is the main product of the SMN1 gene.  Short SMN protein is the main product of the SMN2 gene.
2. In SMA, the SMN1 gene is missing, which vastly decreases the amount of full-length SMN protein.
3. The goal of drug treatment is to increase the amount of full-length SMN protein produced from the SMN2 gene.
   

For Families of SMA, deCODE chemistry focused on optimizing drug-like properties into a promising series of compounds known as 2,4-diaminoquinazolines, which were first discovered in our high-throughput drug screens at Aurora/Vertex.  In order to do this, deCODE made about 1,000 close relatives of the original compound in a process call lead optimization. 

Lead optimization is a reiterative process whereby compounds found to be more effective than the parent compounds are then further modified until the greatest bioactivity is obtained, toxicities and off-target activities are reduced, and drug-like properties are maximized.  deCODE has now generated optimized analogues that have many of the features of required in a SMA drug: the ability to increase SMN levels in the spinal cord of SMA mice and SMA cellular models, the ability to work at low concentrations, metabolic stability, efficient penetration of the blood-brain barrier, and an attractive pharmacokinetic profile. 

Medicinal Chemistry was used to turn a compound with desired bioactivity in a Petri dish (SMN enhancement) into a practical human drug.  As a result of this process the project team nominated a clinical drug candidate in 2007 to be assessed in a series of experiments required by the FDA to begin human clinical trials. 

In August of 2009, FSMA received FDA Orphan Drug Designation for Quinazoline495, our clinical drug candidate in this program, for the treatment of SMA. Please click here to read more.

1. In 2008, a summary of the lead optimization project was published in the Journal of Medicinal Chemistry.  See the paper abstract here.  
2. In 2008, the protein target, DcpS, being modulated by the quinazoline compounds was identified and published in ACS Chemical Biology.  See the paper abstract here. 
3. In 2009 the first test of the compounds in severe SMA animal models was published in Human Molecular Genetics.  See the paper abstract here. 
4. In 2010, exciting data showing over a 400% increase in survival after drug treatment with the clinical candidate in an intermediate mouse model of SMA was presented at the 40th Annual Society of Neuroscience Meeting. See the meeting abstract here. 
5. In 2011, data was presented at the 41st Annual Society of Neuroscience Meeting on the ability of RG3039 to influence survival and functionality in severe mouse models of SMA, as well as very significantly benefit motor neuron defects seen in severe SMA mice.  Click on the links above to read the 2011 meeting abstracts.