Discovery and Optimization of Small Molecule Splicing Modifiers of Survival Motor Neuron 2 as a Treatment for Spinal Muscular Atrophy.
The underlying cause of spinal muscular atrophy (SMA) is a deficiency of the survival motor neuron (SMN) protein. Starting from hits identified in a high-throughput screening campaign and through structure-activity relationship investigations, we have developed small molecules that potently shift the alternative splicing of the SMN2 exon 7, resulting in increased production of the full-length SMN mRNA and protein. Three novel chemical series, represented by compounds 9, 14, and 20, have been optimized to increase the level of SMN protein by >50% in SMA patient-derived fibroblasts at concentrations of <160 nM. Daily administration of these compounds to severe SMA Δ7 mice results in an increased production of SMN protein in disease-relevant tissues and a significant increase in median survival time in a dose-dependent manner. Our work supports the development of an orally administered small molecule for the treatment of patients with SMA.
PTC Therapeutics, Inc. , 100 Corporate Court, South Plainfield, New Jersey 07080, United States.
Matthew G
MG
Woll
PTC Therapeutics, Inc. , 100 Corporate Court, South Plainfield, New Jersey 07080, United States.
Hongyan
H
Qi
PTC Therapeutics, Inc. , 100 Corporate Court, South Plainfield, New Jersey 07080, United States.
Anthony
A
Turpoff
PTC Therapeutics, Inc. , 100 Corporate Court, South Plainfield, New Jersey 07080, United States.
Nanjing
N
Zhang
PTC Therapeutics, Inc. , 100 Corporate Court, South Plainfield, New Jersey 07080, United States.
Xiaoyan
X
Zhang
PTC Therapeutics, Inc. , 100 Corporate Court, South Plainfield, New Jersey 07080, United States.
Guangming
G
Chen
PTC Therapeutics, Inc. , 100 Corporate Court, South Plainfield, New Jersey 07080, United States.
Chunshi
C
Li
PTC Therapeutics, Inc. , 100 Corporate Court, South Plainfield, New Jersey 07080, United States.
Song
S
Huang
PTC Therapeutics, Inc. , 100 Corporate Court, South Plainfield, New Jersey 07080, United States.
Tianle
T
Yang
PTC Therapeutics, Inc. , 100 Corporate Court, South Plainfield, New Jersey 07080, United States.
Young-Choon
YC
Moon
PTC Therapeutics, Inc. , 100 Corporate Court, South Plainfield, New Jersey 07080, United States.
Chang-Sun
CS
Lee
PTC Therapeutics, Inc. , 100 Corporate Court, South Plainfield, New Jersey 07080, United States.
Soongyu
S
Choi
PTC Therapeutics, Inc. , 100 Corporate Court, South Plainfield, New Jersey 07080, United States.
Neil G
NG
Almstead
PTC Therapeutics, Inc. , 100 Corporate Court, South Plainfield, New Jersey 07080, United States.
Nikolai A
NA
Naryshkin
PTC Therapeutics, Inc. , 100 Corporate Court, South Plainfield, New Jersey 07080, United States.
Amal
A
Dakka
PTC Therapeutics, Inc. , 100 Corporate Court, South Plainfield, New Jersey 07080, United States.
Jana
J
Narasimhan
PTC Therapeutics, Inc. , 100 Corporate Court, South Plainfield, New Jersey 07080, United States.
Vijayalakshmi
V
Gabbeta
PTC Therapeutics, Inc. , 100 Corporate Court, South Plainfield, New Jersey 07080, United States.
Ellen
E
Welch
PTC Therapeutics, Inc. , 100 Corporate Court, South Plainfield, New Jersey 07080, United States.
Xin
X
Zhao
PTC Therapeutics, Inc. , 100 Corporate Court, South Plainfield, New Jersey 07080, United States.
Nicole
N
Risher
PTC Therapeutics, Inc. , 100 Corporate Court, South Plainfield, New Jersey 07080, United States.
Josephine
J
Sheedy
PTC Therapeutics, Inc. , 100 Corporate Court, South Plainfield, New Jersey 07080, United States.
Marla
M
Weetall
PTC Therapeutics, Inc. , 100 Corporate Court, South Plainfield, New Jersey 07080, United States.
Gary M
GM
Karp
D017398:Alternative Splicing / Q000187:drug effects*; D000818:Animals; D002460:Cell Line; D055808:Drug Discovery; D005091:Exons / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D018345:Mice, Knockout; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D054852:Small Molecule Libraries / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics
D012333:RNA, Messenger; C526477:SMN2 protein, human; D054852:Small Molecule Libraries; D055540:Survival of Motor Neuron 2 Protein