(S)-PHA533533

(S)-PHA533533 is a CDK2 and CDK5 inhibitor with blood-brain barrier permeability, with IC₅₀ values of 37 nM and 55 nM, respectively. (S)-PHA533533 effectively restores UBE3A expression by downregulating UBE3A-ATS and relieving the epigenetic silencing of paternal UBE3A in mature neurons. (S)-PHA533533 can be used for the research of Angelman syndrome^[1].
In Vitro, (S)-PHA533533 (1 μM; 72 h) potently activates paternal Ube3a expression in primary cortical neurons from Ube3a^m+/pYFP mice^[1].
(S)-PHA533533 (72 h) activates paternal Ube3a expression in primary cortical neurons from Ube3am+/pYFP mice, with an EC₅₀ of 0.54 μM, an E_MAX of 80.02% paternal UBE3A-YFP-positive neurons, and a CC₅₀ of 2.98 μM^[1].
(S)-PHA533533 (1 μM; 72 h) activates paternal Ube3a expression in primary cortical neurons derived from Ube3a^m+/pYFP mice, and this process is independent of the inhibition of CDK2, CDK5 and TOP1^[1].
(S)-PHA533533 (72 h) downregulates UBE3A-ATS and relieves the silencing of paternal UBE3A in forebrain cortical neurons derived from ASdel1-0ΔI-P human induced pluripotent stem cells, with an EC₅₀ of 0.59 μM for UBE3A induction and an IC₅₀ of 0.42 μM for UBE3A-ATS downregulation^[1].
In Vivo, (S)-PHA533533 (2 mg/kg; i.p.; single injection) produces brain-wide unsilencing of paternal Ube3a, significantly increasing Ube3a mRNA and UBE3A protein levels in neurons of Angelman syndrome model mice^[1].

References:
[1]. Vihma H, et al. Ube3a unsilencer for the potential treatment of Angelman syndrome. Nat Commun. 2024;15(1):5558. Published 2024 Jul 8.