"目录号: HY-14832
Membrane Transporter/Ion Channel-
PTC124靶向作用于无义突变，将终止密码子插入到CFTR基因中间。
CFTR
相关产品
VX-809-Ivacaftor-CFTR(inh)-172-GlyH-101-VX-661-BPO-27 racemate-IOWH-032-PPQ-102-KM11060-
生物活性
Description
PTC124 targets nonsense mutations, which insert a termination codon in the middle of theCFTRgene.
IC50& Target
CFTR[1]
In Vitro
This premature “stop” signal (a class I mutation) prevents the cell from producing a full-length CFTR protein[1]. PTC124 (Ataluren)-a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons[2].
In Vivo
PTC124 (Ataluren) activity, optimized using nonsense-containing reporters, promotes dystrophin production in primary muscle cells from humans andmdxmice expressing dystrophin nonsense alleles, and rescues striated muscle function inmdxmice within 2-8?weeks of drug exposure. PTC124 is well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression[2]. To induce nonsense suppression and increase PPT1 enzyme activity, the read-through drug PTC124 (Ataluren) is given via intraperitoneal (i.p.) injection to maleCln1R151Xmice at 2 months of age. These treatments are performed four times daily for 2 consecutive days in a proof-of-principle study. Used at 10 mg/kg, PTC124 increased PPT1 enzyme activity (P=0.0001 by unpaired t-test) and protein level (P=0.0014 by unpaired t-test) in the liver, but did not increase PPT1 enzyme activity or protein level in the cortex. This tissue-specific effect is likely due to the inability of PTC124 to breach the blood brain barrier (BBB), which decreased the bioavailability of PTC124 within the brain, and prevented PTC124 from reaching an efficacious concentration within the therapeutic window[3].
Clinical Trial
NCT02456103
PTC Therapeutics
Cystic Fibrosis
July 2015
Phase 3
NCT02819557
PTC Therapeutics
Duchenne Muscular Dystrophy
June 2016
Phase 2
NCT02090959
PTC Therapeutics
Muscular Dystrophy, Duchenne-Muscular Dystrophies-Muscular Disorders, Atrophic-Muscular Diseases-Musculoskeletal Diseases-Neuromuscular Diseases-Nervous System Diseases-Genetic Diseases, X-Linked-Genetic Diseases, Inborn
March 2014
Phase 3
NCT02758626
New York University School of Medicine-PTC Therapeutics
Epilepsy
November 2016
Phase 2
NCT01557400
PTC Therapeutics
Duchenne Muscular Dystrophy-Becker Muscular Dystrophy-Dystrophinopathy
May 2012
Phase 3
NCT01009294
PTC Therapeutics-Genzyme, a Sanofi Company
Duchenne Muscular Dystrophy-Becker Muscular Dystrophy
November 2009
Phase 2
NCT01140451
PTC Therapeutics-Cystic Fibrosis Foundation Therapeutics
Cystic Fibrosis
August 2010
Phase 3
NCT00759876
PTC Therapeutics-Genzyme, a Sanofi Company
Duchenne Muscular Dystrophy
July 2008
Phase 2
NCT00847379
PTC Therapeutics-Genzyme, a Sanofi Company
Duchenne Muscular Dystrophy-Becker Muscular Dystrophy
January 2009
Phase 2-Phase 3
NCT01826487
PTC Therapeutics
Muscular Dystrophy, Duchenne-Muscular Dystrophies-Muscular Disorders, Atrophic-Muscular Diseases-Musculoskeletal Diseases-Neuromuscular Diseases-Nervous System Diseases-Genetic Diseases, X-Linked-Genetic Diseases, Inborn
March 2013
Phase 3
NCT00803205
PTC Therapeutics-Cystic Fibrosis Foundation Therapeutics
Cystic Fibrosis
July 2009
Phase 3
NCT01247207
PTC Therapeutics
Duchenne Muscular Dystrophy-Becker Muscular Dystrophy
November 2010
Phase 3
NCT02647359
PTC Therapeutics
Aniridia
January 2016
Phase 2
NCT02107859
PTC Therapeutics
Cystic Fibrosis
May 2014
Phase 3
NCT01141075
PTC Therapeutics-Genzyme, a Sanofi Company
Amino Acid Metabolism, Inborn Errors
June 2010
Phase 2
NCT03179631
PTC Therapeutics
Muscular Dystrophy, Duchenne-Muscular Dystrophies-Muscular Disorders, Atrophic-Muscular Diseases-Musculoskeletal Disease-Neuromuscular Diseases-Nervous System Diseases-Genetic Diseases, X-Linked-Genetic Diseases, Inborn
July 6, 2017
Phase 3
NCT00947193
PTC Therapeutics-Genzyme, a Sanofi Company
Hemophilia A-Hemophilia B
August 2009
Phase 2
NCT02409004
PTC Therapeutics
Healthy
March 2015
Phase 1
NCT02139306
PTC Therapeutics-Cystic Fibrosis Foundation Therapeutics-European Cystic Fibrosis Society-Clinical Trial Network (ECFS-CTN)
Cystic Fibrosis
June 2014
Phase 3
NCT02456103
PTC Therapeutics
Cystic Fibrosis
July 2015
Phase 3
NCT02819557
PTC Therapeutics
Duchenne Muscular Dystrophy
June 2016
Phase 2
NCT02090959
PTC Therapeutics
Muscular Dystrophy, Duchenne-Muscular Dystrophies-Muscular Disorders, Atrophic-Muscular Diseases-Musculoskeletal Diseases-Neuromuscular Diseases-Nervous System Diseases-Genetic Diseases, X-Linked-Genetic Diseases, Inborn
March 2014
Phase 3
NCT02758626
New York University School of Medicine-PTC Therapeutics
Epilepsy
November 2016
Phase 2
NCT01557400
PTC Therapeutics
Duchenne Muscular Dystrophy-Becker Muscular Dystrophy-Dystrophinopathy
May 2012
Phase 3
NCT01009294
PTC Therapeutics-Genzyme, a Sanofi Company
Duchenne Muscular Dystrophy-Becker Muscular Dystrophy
November 2009
Phase 2
NCT01140451
PTC Therapeutics-Cystic Fibrosis Foundation Therapeutics
Cystic Fibrosis
August 2010
Phase 3
NCT00759876
PTC Therapeutics-Genzyme, a Sanofi Company
Duchenne Muscular Dystrophy
July 2008
Phase 2
NCT00847379
PTC Therapeutics-Genzyme, a Sanofi Company
Duchenne Muscular Dystrophy-Becker Muscular Dystrophy
January 2009
Phase 2-Phase 3
NCT01826487
PTC Therapeutics
Muscular Dystrophy, Duchenne-Muscular Dystrophies-Muscular Disorders, Atrophic-Muscular Diseases-Musculoskeletal Diseases-Neuromuscular Diseases-Nervous System Diseases-Genetic Diseases, X-Linked-Genetic Diseases, Inborn
March 2013
Phase 3
NCT00803205
PTC Therapeutics-Cystic Fibrosis Foundation Therapeutics
Cystic Fibrosis
July 2009
Phase 3
NCT01247207
PTC Therapeutics
Duchenne Muscular Dystrophy-Becker Muscular Dystrophy
November 2010
Phase 3
NCT02647359
PTC Therapeutics
Aniridia
January 2016
Phase 2
NCT02107859
PTC Therapeutics
Cystic Fibrosis
May 2014
Phase 3
NCT01141075
PTC Therapeutics-Genzyme, a Sanofi Company
Amino Acid Metabolism, Inborn Errors
June 2010
Phase 2
NCT03179631
PTC Therapeutics
Muscular Dystrophy, Duchenne-Muscular Dystrophies-Muscular Disorders, Atrophic-Muscular Diseases-Musculoskeletal Disease-Neuromuscular Diseases-Nervous System Diseases-Genetic Diseases, X-Linked-Genetic Diseases, Inborn
July 6, 2017
Phase 3
NCT00947193
PTC Therapeutics-Genzyme, a Sanofi Company
Hemophilia A-Hemophilia B
August 2009
Phase 2
NCT02409004
PTC Therapeutics
Healthy
March 2015
Phase 1
NCT02139306
PTC Therapeutics-Cystic Fibrosis Foundation Therapeutics-European Cystic Fibrosis Society-Clinical Trial Network (ECFS-CTN)
Cystic Fibrosis
June 2014
Phase 3
NCT00592553
PTC Therapeutics
Duchenne Muscular Dystrophy-Becker Muscular Dystrophy
February 2008
Phase 2-Phase 3
NCT00264888
PTC Therapeutics-Muscular Dystrophy Association
Duchenne Muscular Dystrophy
December 2005
Phase 2
NCT00351078
PTC Therapeutics
Cystic Fibrosis
December 2006
Phase 2
NCT00234663
PTC Therapeutics-Cystic Fibrosis Foundation Therapeutics-FDA Office of Orphan Products Development
Cystic Fibrosis
September 2005
Phase 2
NCT00458341
PTC Therapeutics
Cystic Fibrosis
March 2007
Phase 2
NCT00237380
PTC Therapeutics
Cystic Fibrosis
November 2005
Phase 2
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References
[1].Pettit RS, et al. CFTR Modulators for the Treatment of Cystic Fibrosis. P T. 2014 Jul;39(7):500-11.
[2].Welch EM, et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature, 2007, 447(7140), 87-91.
[3].Miller JN, et al. The novel Cln1(R151X) mouse model of infantile neuronal ceroid lipofuscinosis (INCL) for testing nonsense suppression therapy. Hum Mol Genet. 2015 Jan 1;24(1):185-96.