SK5527 is a selective AURKA PROTAC degrader that targets and degrades the AURKA protein, exhibiting a DC50 of 2 nM. It binds to NanoLuc-AURKA with an IC50 of 20 nM. In MYCN-amplified neuroblastoma cells, SK5527 effectively reduces MYCN levels, but its activity is constrained by MDR1-mediated efflux. In vivo, it efficiently lowers AURKA levels. SK5527 serves as a useful tool for neuroblastoma research.

Aurora A:2 nM (DC50)

SK5527, tested in concentrations ranging from 0.01 to 10000 nM for 1-48 hours, effectively induces degradation of AURKA and MYCN in neuroblastoma and benign cell lines (HEK293T, RPE). It demonstrates high potency in MYCN amplified cells (IMR-32, NGP, SJNB-8, SK-N-BE(2)-C) with DC50 values of 6, 2, 10, and 73 nM, respectively, while decreasing activity is observed in other cell lines (SK-N-BE(2)-C, SK-N-AS, SJNB-1) along with a hook effect. The depletion of MYCN occurs as a secondary delayed event post-AURKA degradation, necessitating the binding of both AURKA and CRBN for the degradation action to be effective, with GI50 values of 15, 21, 63, and 477 nM in IMR-32, NGP, SJNB-8, and SK-N-BE(2)-C, respectively. In non-amplified cells (SK-N-SH, SK-N-AS, SJNB-1) and benign immortalized cells like RPE and HEK293T, GI50 values are 244, 654, 8635, 460, and 408 nM, respectively. At concentrations of 10-10000 nM for 72 hours, SK5527 inhibits the growth of neuroblastoma cells (IMR-32, NGP, SJNB-8, SK-N-SH, SK-N-BE(2)-C, SJNB-1). Its action at 100-1000 nM over 3 hours requires concurrent binding to AURKA and CRBN, displaying significant affinity for AURKA and excellent selectivity across the kinase panel, while upregulating PLK1 and downregulating HAND2 and ESCO2, but not affecting GSPT1, CSNK1A1, ZFP91, SALL4, ZNF654, ZNF787, E4F1, and PATZ1. Although SK5527 effectively degrades AURKA with a DC50 of approximately 0.5 μM, it shows moderate inhibitory effects in benign immortalized cell lines HEK293T and RPE. The compound's activity in SK-N-SH, SK-N-BE(2)-C, SJNB-1, NGP, SJNB-8, IMR-32 is constrained by MDR1-mediated drug efflux, although this limitation is absent in SK-N-AS cells due to low CRBN expression.

A single administration of SK5527 (15 mg/kg, administered intravenously or intraperitoneally) induces depletion of AURKA protein in a CDX mouse model derived from the IMR-32 neuroblastoma cell line.