Discovery of Small Molecule Splicing Modulators of Survival Motor Neuron-2 (SMN2) for the Treatment of Spinal Muscular Atrophy (SMA)

被引：89

作者：

Cheung, Atwood K. ^{[1
]}

Hurley, Brian ^{[1
]}

Kerrigan, Ryan ^{[1
]}

Shu, Lei ^{[1
]}

Chin, Donovan N. ^{[1
,4
]}

Shen, Yiping ^{[1
]}

O'Brien, Gary ^{[1
]}

Sung, Moo Je ^{[1
]}

Hou, Ying ^{[1
]}

Axford, Jake ^{[1
]}

Cody, Emma ^{[1
]}

Sun, Robert ^{[1
,5
]}

Fazal, Aleem ^{[1
]}

Fridrich, Cary ^{[1
]}

Sanchez, Carina C. ^{[1
]}

Tomlinson, Ronald C. ^{[1
,6
]}

Jain, Monish ^{[1
]}

Deng, Lin ^{[1
]}

Hoffmaster, Keith ^{[1
]}

Song, Cheng ^{[1
,7
]}

Van Hoosear, Mailin ^{[1
,8
]}

Shin, Youngah ^{[1
]}

Servais, Rebecca ^{[1
]}

Towler, Christopher ^{[2
]}

Hild, Marc ^{[1
]}

Curtis, Daniel ^{[1
,9
]}

Dietrich, William F. ^{[1
]}

Hamann, Lawrence G. ^{[1
,10
]}

Briner, Karin ^{[1
]}

Chen, Karen S. ^{[3
]}

Kobayashi, Dione ^{[3
,11
]}

Sivasankaran, Rajeev ^{[1
]}

Dales, Natalie A. ^{[1
]}

机构：

[1] Novartis Inst BioMed Res, 250 Massachusetts Ave, Cambridge, MA 02139 USA

[2] Novartis Pharmaceut, 250 Massachusetts Ave, Cambridge, MA 02139 USA

[3] SMA Fdn, 888 Seventh Ave,Suite 400, New York, NY 10019 USA

[4] Arrakis Therapeut, 35 Gatehouse Dr, Waltham, MA 02451 USA

[5] Tesaro, 1000 Winter St, Waltham, MA 02451 USA

[6] AstraZeneca, 35 Gatehouse Dr, Waltham, MA 02451 USA

[7] Merck Res Labs, 33 Ave Louis Pasteur, Boston, MA 02115 USA

[8] Appl Genetic Technol Corp, 14193 NW 119th Terrace, Alachua, FL 32615 USA

[9] AmylonTherapeut, One Broadway,14th Floor, Cambridge, MA 02142 USA

[10] Celgene Corp, 200 Cambridge Pk Dr,Suite 3000, Cambridge, MA 02140 USA

[11] AkeOla LLC, 27 Beech St, Cambridge, MA 02140 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 61卷 / 24期

关键词：

SINGLE NUCLEOTIDE; IDENTIFICATION; MODIFIERS;

D O I：

10.1021/acs.jmedchem.8b01291

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Spinal muscular atrophy (SMA), a rare neuromuscular disorder, is the leading genetic cause of death in infants and toddlers. SMA is caused by the deletion or a loss of function mutation of the survival motor neuron 1 (SMN1) gene. In humans, a second closely related gene SMN2 exists; however it codes for a less stable SMN protein. In recent years, significant progress has been made toward disease modifying treatments for SMA by modulating SMN2 pre-mRNA splicing. Herein, we describe the discovery of LMI070/branaplam, a small molecule that stabilizes the interaction between the spliceosome and SMN2 pre-mRNA. Branaplam (1) originated from a high-throughput phenotypic screening hit, pyridazine 2, and evolved via multiparameter lead optimization. In a severe mouse SMA model, branaplam treatment increased full-length SMN RNA and protein levels, and extended survival. Currently, branaplam is in clinical studies for SMA.

引用

页码：11021 / 11036

页数：16

共 32 条

[1] Designing libraries with CNS activity [J].

Ajay ;

Bemis, GW ;

Murcko, MA .

JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (24) :4942-4951

[2] Identification of broad-spectrum antiviral compounds and assessment of the druggability of their target for efficacy against respiratory syncytial virus (RSV) [J].

Bonavia, Aurelio ;

Franti, Michael ;

Keaney, Erin Pusateri ;

Kuhen, Kelli ;

Seepersaud, Mohindra ;

Radetich, Branko ;

Shao, Jian ;

Honda, Ayako ;

Dewhurst, Janetta ;

Balabanis, Kara ;

Monroe, James ;

Wolff, Karen ;

Osborne, Colin ;

Lanieri, Leanne ;

Hoffmaster, Keith ;

Amin, Jakal ;

Markovits, Judit ;

Broome, Michelle ;

Skuba, Elizabeth ;

Cornella-Taracido, Ivan ;

Joberty, Gerard ;

Bouwmeester, Tewis ;

Hamann, Lawrence ;

Tallarico, John A. ;

Tommasi, Ruben ;

Compton, Teresa ;

Bushell, Simon M. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2011, 108 (17) :6739-6744

[3] Strong Conformational Preferences of Heteroaromatic Ethers and Electron Pair Repulsion [J].

Chein, Rong-Jie ;

Corey, E. J. .

ORGANIC LETTERS, 2010, 12 (01) :132-135

[4] Identification and structure-activity relationships of substituted pyridones as inhibitors of Pim-1 kinase [J].

Cheney, I. Wayne ;

Yan, Shunqi ;

Appleby, Todd ;

Walker, Hell ;

Vo, Todd ;

Yao, Nanhua ;

Hamatake, Robert ;

Hong, Zhi ;

Wu, Jim Z. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2007, 17 (06) :1679-1683

[5] Results from a phase 1 study of nusinersen (ISIS-SMNRx) in children with spinal muscular atrophy [J].

Chiriboga, Claudia A. ;

Swoboda, Kathryn J. ;

Darras, Basil T. ;

Iannaccone, Susan T. ;

Montes, Jacqueline ;

De Vivo, Darryl C. ;

Norris, Daniel A. ;

Bennett, C. Frank ;

Bishop, Kathie M. .

NEUROLOGY, 2016, 86 (10) :890-897

[6] Demystifying Brain Penetration in Central Nervous System Drug Discovery [J].

Di, Li ;

Rong, Haojing ;

Feng, Bo .

JOURNAL OF MEDICINAL CHEMISTRY, 2013, 56 (01) :2-12

[7] Identification of a battery of tests for drug candidate evaluation in the SMNΔ7 neonate model of spinal muscular atrophy [J].

El-Khodor, Bassern F. ;

Edgar, Nicole ;

Chen, Angela ;

Winberg, Margaret L. ;

Joyce, Cynthia ;

Brunner, Daniela ;

Suarez-Farinas, Mayte ;

Heyes, Melvyn P. .

EXPERIMENTAL NEUROLOGY, 2008, 212 (01) :29-43

[8] The impact of drug-induced qt interval prolongation on drug discovery and development [J].

Fermini, B ;

Fossa, AA .

NATURE REVIEWS DRUG DISCOVERY, 2003, 2 (06) :439-447

[9] Differential SMN2 expression associated with SMA severity [J].

Gavrilov, DK ;

Shi, XY ;

Das, K ;

Gilliam, TC ;

Wang, CH .

NATURE GENETICS, 1998, 20 (03) :230-231

[10] Synthesis and evaluation of 3-amino-6-aryl-pyridazines as selective CB2 agonists for the treatment of inflammatory pain [J].

Gleave, Robert J. ;

Beswick, Paul J. ;

Brown, Andrew J. ;

Giblin, Gerard M. P. ;

Goldsmith, Paul ;

Haslam, Carl P. ;

Mitchell, William L. ;

Nicholson, Neville H. ;

Page, Lee W. ;

Patel, Sadhana ;

Roomans, Susan ;

Slingsby, Brian P. ;

Swarbrick, Martin E. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2010, 20 (02) :465-468

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