MD-224, a highly potent PROTAC degrader of MDM2 that is composed of Cereblon and MDM2 ligand, induces rapid degradation of the MDM2 protein [1]. MD-224 binds to the pregnane X receptor (PXR) outside the ligand-binding pocket at a structural motif and can induce the degradation of multiple nuclear receptors[2]. MD-224 has been widely used to inhibit the growth of tumor cells in a p53-independent manner and induce tumor regression in mouse xenograft models[3].
In vitro, MD-224 treatment for 4 days significantly inhibited the proliferation of RS4;11 cells, with an IC50 value of 1.5nM[4].
In vivo, MD-224 treatment via intravenous injection at a dose of 50mg/kg, once every other day for 3 weeks, significantly inhibited tumor growth in the RS4;11 xenograft mouse model without causing weight loss in the mice[4].
References:
[1] Yang J, Li Y, Aguilar A, et al. Simple structural modifications converting a bona fide MDM2 PROTAC degrader into a molecular glue molecule: a cautionary tale in the design of PROTAC degraders[J]. Journal of medicinal chemistry, 2019, 62(21): 9471-9487.
[2] Huber A D, Lin W, Jung Y H, et al. PROTAC repurposing uncovers a noncanonical binding surface that mediates chemical degradation of nuclear receptors[J]. Nature Communications, 2025, 16(1): 9805.
[3] Han X, Wei W, Sun Y. PROTAC degraders with ligands recruiting MDM2 E3 ubiquitin ligase: an updated perspective[J]. Acta materia medica, 2022, 1(2): 244.
[4] Li Y, Yang J, Aguilar A, et al. Discovery of MD-224 as a first-in-class, highly potent, and efficacious proteolysis targeting chimera murine double minute 2 degrader capable of achieving complete and durable tumor regression[J]. Journal of medicinal chemistry, 2018, 62(2): 448-466.
MD-224 是一种作用强大的MDM2蛋白降解剂，由Cereblon和MDM2配体组成，能够促使MDM2蛋白迅速降解[1]。MD-224能够以特定的结构基序结合pregnane X receptor (PXR)（位于配体结合口袋之外），并可诱导多种核受体的降解[2]。MD-224已被广泛用于以不依赖p53的方式抑制肿瘤细胞生长，并在小鼠异种移植模型中诱导肿瘤消退[3]。
在体外，MD-224处理RS4;11细胞4天，显著抑制了细胞增殖，IC50值为1.5nM[5]。
在体内，MD-224通过静脉注射给药，剂量为50mg/kg，每隔一天一次，持续3周，显著抑制了RS4;11异种移植小鼠模型中的肿瘤生长，且未导致小鼠体重减轻[4]。