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

  • J Med Chem. 2026 May 28;69(10):12260-12290. doi: 10.1021/acs.jmedchem.6c00168.
Anna Welton-Arndt  1 ,  Hannah C Nourie  2 ,  Hanna Vihma  2 ,  Siyuan Liang  2 ,  Jonathan Super  1 ,  Kelin Li  3 ,  Jon L Collins  4 ,  Hsueh-Cheng Huang  5 ,  Allison Zhang  1 ,  Ashley E Trojniak  3 ,  Benjamin D Philpot  2 ,  Jeffrey Aubé  1  3
Affiliations
  • 1. Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 2. Department of Cell Biology and Physiology, Neuroscience Center, and Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 3. Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 4. Office of the Vice Chancellor for Research, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 5. Deerfield Discovery and Development, Deerfield Management, New York, New York 10010-1707, United States.
PMID: 42102319 DOI: 10.1021/acs.jmedchem.6c00168
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.

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