Work

Toward a Small Molecule Therapy for Angelman Syndrome: Structure–Activity Relationship Studies of 3-Aminopyrazole Phenylacetamides as Paternal Ube3a Unsilencers

Year: 2026

Type: article

Abstract: Unsilencing of paternal UBE3A is presently the leading therapeutic strategy for Angelman syndrome, a neurodevelopmental disorder caused by mutation or deletion of maternal UBE3A . Previous work identified ( S )-PHA533533 (( S )- 3 ) as a small molecule unsilencer of paternal UBE3A that disrupts UBE3A-ATS, the long noncoding antisense transcript that suppresses paternal UBE3A expression in mature neurons. Initial studies demonstrated that four ( S )- 3 analogs possess unsilencing behavior, which spurred further interest in the 3-aminopyrazole phenylacetamide (APPA) scaffold. Here, we leveraged mouse primary neurons harboring a sensitive reporter of paternal Ube3a expression to establish structure–activity relationships between APPAs, unsilencing behavior, and undesired cellular toxicity. We uncovered compounds with improved potency and less cytotoxicity than hit ( S )- 3 and report a concise set of identification efforts. We demonstrate that the most promising APPAs are 3′ biased in their transcriptional disruption of Ube3a-ATS. Overall, this work provides a basis for additional development of APPAs.

Source: Journal of Medicinal Chemistry

DOI: 10.1021/acs.jmedchem.6c00168