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Small Molecule Screen Reveals Regulation of Survival Motor Neuron Protein Abundance by Ras Proteins

Small Molecule Screen Reveals Regulation of Survival Motor Neuron Protein Abundance by Ras Proteins

Reka R Letso, Andras J Bauer, Mitchell R Lunn, Wan Seok Yang, Brent R Stockwell

ACS Chem Biol. 2013 May 17;8(5):914-22.

PMID: 23496866

Abstract:

Small molecule modulators of protein activity have proven invaluable in the study of protein function and regulation. While inhibitors of protein activity are relatively common, small molecules that can increase protein abundance are rare. Small molecule protein upregulators with targeted activities would be of value in the study of the mechanisms underlying loss-of-function diseases. We developed a high-throughput screening approach to identify small molecule upregulators of the Survival of Motor Neuron protein (SMN), whose decreased levels cause the neurodegenerative disease spinal muscular atrophy (SMA). We screened 69,189 compounds for SMN upregulators and performed mechanistic studies on the most active compound, a bromobenzophenone analogue designated cuspin-1. Mechanistic studies of cuspin-1 revealed that increasing Ras signaling upregulates SMN protein abundance via an increase in translation rate. These findings suggest that controlled modulation of the Ras signaling pathway may benefit patients with SMA.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP337932293	Cuspin-1		337932-29-3	Price

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