RG3039 [5-((1-(2,6-dichlorobenzyl)piperidin-4-yl)methoxy)quinazoline-2,4-diamine]
is orally bioavailable, brain-penetrant small molecule that has been shown to
be an inhibitor of the mRNA decapping enzyme, DcpS. The pharmacological
characterization of RG3039, demonstrates RG3039 can extend survival, improve
function, and impact neuromuscular pathology in three Spinal Muscular Atrophy (SMA)
mouse models of varying disease severity.
RG3039
has the potential to be the first in its class for the treatment of SMA. SMA is
an inherited neurodegenerative disease in which a defect in the SMN1
("survival motor neuron") gene results in low levels of the protein
SMN and leads to progressive damage to motor neurons and loss of muscle
function. Patients lacking a functional SMN1 gene survive only because humans
carry a second gene, known as SMN2, which produces an identical protein, but at
much lower levels. Genetic analysis of SMA patients has shown a striking
correlation between disease severity and the number of copies of the SMN2 gene
carried by the patient. Patients with two copies of the SMN2 gene develop
severe disease while patients with four copies develop few symptoms before
adulthood. The average life expectancy of a patient carrying twos copies of the
SMN2 gene is approximately two years, while the average life expectancy of
patients carrying four copies of the gene is approximately fifty years.
Doubling the gene copy number dramatically alters disease course, suggesting
that a therapy that increases the level of SMN protein in motor neurons may
provide a clinical benefit to patients fighting this debilitating disease. RG3039
increased the production of SMN in preclinical studies of cells derived from
patients.
In 2009, Repligen
in-licensed the SMA program from Families of SMA (FSMA), a patient organization
dedicated to supporting research to advance therapies for SMA. FSMA funded and
directed the preclinical development of the program’s lead compound, RG3039. In January 2013, Pfizer licensed the program
to further develop potential treatments for SMA. The Muscular Dystrophy
Association also provided critical support to Repligen's research and clinical
efforts. The lead compound is currently
being tested in Phase 1b human clinical trials.
Common Name: RG3039
Synonyms: RG3039; RG 3039; RG-3039; PF-06687859; PF
06687859; PF06687859
IUPAC Name: 5-((1-(2,6-dichlorobenzyl)piperidin-4-yl)methoxy)quinazoline-2,4-diamine
CAS Number: 1005504-62-0; 1466525-84-7 (di-hydrochloride)
Mechanism of Action: DcpS Inhibitor
Indication: Treatment of SMA
Development Stage: Phase I
Company: Repligen/Pfizer
What is Spinal
Muscular Atrophy?
Spinal Muscular Atrophy is the second most common inherited
neuromuscular disease. The disease is characterized by loss of motor neurons
that result in the loss of muscle function, and, in many patients, early death.
Symptoms of SMA typically emerge before the age of two and often progress to
severe physical disability or loss of life. SMA is diagnosed in approximately
one in every 6,000 births in the United States and Europe, where the estimated
prevalence is approximately 20,000 patients. There is currently no treatment or
cure for SMA.
