(S)-PHA533533 is a potent, small molecule unsilencer of paternal UBE3A in mouse primary neurons with EC50 of 0.54 uM, Emax=80%, effectively downregulates Ube3a-ATS/UBE3A ATS and epigenetically unsilences paternal Ube3a/UBE3A in both mouse and human neuron.
(S)-PHA533533 is a compound previously developed as a cyclin-dependentkinase 2 (CDK2) inhibitor.
(S)-PHA533533 downregulate a long non-coding anti sense (UBE3A-ATS) transcript and unsilences paternal Ube3a in primary neurons derived from AS model mice (Ube3am–/p+).
(S)-PHA533533 downregulated the Ube3a-ATS similarly to topotecan, significantly increased Ube3a mRNA and protein levels in WT neurons.
The unsilencing of paternal Ube3a by (S)-PHA533533 occurs independently from its known CDK2/CKD5 targets and topoi somerase I inhibition.
Peripheral delivery of (S)-PHA533533 (2mg/kg) can produce brain-wide unsilencing of paternal Ube3a in AS model mice.
(S)-PHA533533 reduces the expression on UBE3A ATS in human ASdel1-0ΔI-P neurons with IC50 of 0.42 uM, EC50 of 0.59 uM for for unsilencing paternal UBE3A.
(S)-PHA533533 downregulates the UBE3A antisense (UBE3A-ATS) transcript and increases paternal UBE3A mRNA in neurons derived from patients with Angelman syndrome.