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

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