ZXH-4-130 is a potent and selective CRBN degrader, functioning as a hetero-PROTAC compound with the inclusion of CRBN-VHL.

Pre-treatment with ZXH-4-130 at concentrations of 100 nM for 2 hours, followed by a 96-hour exposure to 1 μM Pomalidomide, significantly mitigates the cytotoxic effects of Pomalidomide in MM1.S cells, demonstrating a statistically significant protective effect. Furthermore, a 2-hour pre-treatment with 50 nM ZXH-4-130 effectively prevents the degradation of GSPT1, which is induced by CC-885 through the recruitment of CRBN E3 ligase, underscoring the compound's ability to preserve GSPT1 levels. Additionally, a 2-hour pre-treatment with 100 nM ZXH-4-130 followed by a 6-hour exposure to THAL-SNS-032 substantially degrades CRBN, although it only partially inhibits THAL-SNS-032’s activity against CDK9. These findings are supported by cell viability assays and western blot analysis, which confirm that ZXH-4-130 significantly prevents Pomalidomide-induced cytotoxicity and GSPT1 degradation in MM1.S cells.