Specific Correction of Alternative Survival Motor Neuron 2 Splicing by Small Molecules: Discovery of a Potential Novel Medicine To Treat Spinal Muscular Atrophy.
Spinal muscular atrophy (SMA) is the leading genetic cause of infant and toddler mortality, and there is currently no approved therapy available. SMA is caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene. These mutations or deletions result in low levels of functional SMN protein. SMN2, a paralogous gene to SMN1, undergoes alternative splicing and exclusion of exon 7, producing an unstable, truncated SMNΔ7 protein. Herein, we report the identification of a pyridopyrimidinone series of small molecules that modify the alternative splicing of SMN2, increasing the production of full-length SMN2 mRNA. Upon oral administration of our small molecules, the levels of full-length SMN protein were restored in two mouse models of SMA. In-depth lead optimization in the pyridopyrimidinone series culminated in the selection of compound 3 (RG7800), the first small molecule SMN2 splicing modifier to enter human clinical trials.
pRED, Pharma Research & Early Development, F. Hoffmann-La Roche Ltd. , Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland.
Hasane
H
Ratni
PTC Therapeutics, Inc. , 100 Corporate Court, South Plainfield, New Jersey 07080, United States.
Gary M
GM
Karp
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.
Nikolai A
NA
Naryshkin
SMA Foundation , 888 Seventh Avenue, Suite 400, New York, New York 10019, United States.
Sergey V
SV
Paushkin
SMA Foundation , 888 Seventh Avenue, Suite 400, New York, New York 10019, United States.
Karen S
KS
Chen
SMA Foundation , 888 Seventh Avenue, Suite 400, New York, New York 10019, United States.
Kathleen D
KD
McCarthy
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.
Matthew G
MG
Woll
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.
Nanjing
N
Zhang
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.
Amal
A
Dakka
PTC Therapeutics, Inc. , 100 Corporate Court, South Plainfield, New Jersey 07080, United States.
Priya
P
Vazirani
PTC Therapeutics, Inc. , 100 Corporate Court, South Plainfield, New Jersey 07080, United States.
Xin
X
Zhao
pRED, Pharma Research & Early Development, F. Hoffmann-La Roche Ltd. , Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland.
Emmanuel
E
Pinard
pRED, Pharma Research & Early Development, F. Hoffmann-La Roche Ltd. , Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland.
Luke
L
Green
pRED, Pharma Research & Early Development, F. Hoffmann-La Roche Ltd. , Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland.
Pascale
P
David-Pierson
pRED, Pharma Research & Early Development, F. Hoffmann-La Roche Ltd. , Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland.
Dietrich
D
Tuerck
pRED, Pharma Research & Early Development, F. Hoffmann-La Roche Ltd. , Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland.
Agnes
A
Poirier
pRED, Pharma Research & Early Development, F. Hoffmann-La Roche Ltd. , Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland.
Wolfgang
W
Muster
pRED, Pharma Research & Early Development, F. Hoffmann-La Roche Ltd. , Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland.
Stephan
S
Kirchner
pRED, Pharma Research & Early Development, F. Hoffmann-La Roche Ltd. , Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland.
Lutz
L
Mueller
pRED, Pharma Research & Early Development, F. Hoffmann-La Roche Ltd. , Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland.
Irene
I
Gerlach
pRED, Pharma Research & Early Development, F. Hoffmann-La Roche Ltd. , Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland.
Friedrich
F
Metzger
D017398:Alternative Splicing / Q000187:drug effects*; D000818:Animals; D005091:Exons / Q000187:drug effects; D006801:Humans; D051379:Mice; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy* / Q000235:genetics; D011744:Pyrimidinones / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics*; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics*
D011744:Pyrimidinones; D012333:RNA, Messenger; D055540:Survival of Motor Neuron 2 Protein