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Families of Spinal Muscular Atrophy Funded Program Shows Quinazoline Compounds Give Survival Benefit in a Severe Mouse Model of SMA.

This publication, showing data from the testing of Quinazoline derivatives in a Spinal Muscular Atrophy mouse model, has been published in Human Molecular Genetics by lead author Dr. Matthew Butchbach from the laboratory of Dr. Arthur Burghes at the Ohio State University.

The generation of the Quinazoline compounds as a therapeutic drug candidate for Spinal Muscular Atrophy was fully funded by Families of SMA.

The paper explores whether the Quinazoline compounds, which increase the expression of SMN2, are useful as potential therapeutics for SMA. Ultrahigh-throughput screening identified substituted Quinazolines as potent SMN2 inducers.  The drug-like properties of the initial screening hits were optimized through directed medicinal chemistry.  This resulted in series of C5-Quinazoline derivatives.

Oral administration of three of these compounds (D152344, D153249 and D156844) to neonatal mice resulted in a dose-dependent increase in Smn promoter activity in the central nervous system.  The authors then examined the effect of these compounds on the progression of disease in SMNDelta7 SMA mice.  Oral administration of D156844 significantly increased the mean lifespan of SMNDelta7 SMA mice by approximately 21-30% when given prior to motor neuron loss.  Overall the authors summarize that the quinazoline derivative D156844 increases SMN expression in neonatal mouse neural tissues, delays motor neuron loss at PND11, and ameliorates the motor phenotype of SMNDelta7 SMA mice.

“This is the first compound series to go from hit-to-preclinical candidate that shows favorable pharmacology in the nervous system and shows benefit to severe SMA mice.  This study shows that promising therapies for SMA can be developed”, said Matthew Butchbach, Ph.D., who is lead author on this publication.

“Families of SMA is pleased that the first test of this class of compounds in SMA mice shows potential therapeutic benefit.  The clinical lead in this series called Quinazoline495, which is a more optimized compound than those tested here, has also been assessed in this animal model with similar results, as well as tested in a slightly less severe mouse model of SMA, in which it showed marked enhancement of survival”, says Jill Jarecki, Ph.D., FSMA research director.

The lead compound Quinazoline495 recently received orphan drug designation from the FDA for the treatment of spinal muscular atrophy.  Please click here to read more.

Families of SMA recently licensed this series of compounds to Repligen Corporation for development as a drug treatment for Spinal Muscular Atrophy.

The full reference:

Butchbach ME, Singh J, Thornorsteinsdóttir M, Saieva L, Slominski E, Thurmond J, Andrésson T, Zhang J, Edwards JD, Simard LR, Pellizzoni L, Jarecki J, Burghes AH, Gurney ME. Effects of 2,4-diaminoquinazoline derivatives on SMN expression and phenotype in a mouse model for spinal muscular atrophy. (2009). Human Molecular Genetics, Epub ahead of print.