RG7388 is an orally active MDM2 antagonist (IC50=6nM) that activates the p53 pathway by inhibiting the MDM2-p53 interaction[1-2]. RG7388 can induce cell cycle arrest to reduce tumor cell proliferation and is applicable for research related to acute myeloid leukemia and solid tumors[3-4].
In vitro, treatment of TP53 wild-type T-cell acute lymphoblastic leukemia (T-ALL) cell line MOLT-3 with RG7388 (0-90nM) for 24-72 hours, RG7388 induced p53-dependent stabilization and accumulation of p53 protein, upregulated the expression of the pro-apoptotic BH3 domain genes BAX and BBC3 (PUMA), and increased caspase-3/7 activity and apoptosis[5]. Treatment of colorectal cancer (CRC) cell lines HCT116 and RKO with RG7388 (1µM) for 24 hours, RG7388 induced p53 protein accumulation. In combination with the HSP90 inhibitor Ganetespib (50nM), RG7388 synergistically reduced cell viability and confluence, and increased cell death and PARP-1 cleavage[6].
In vivo, oral co-administration of RG7388 (40-75mg/kg) with the ALK inhibitor Lorlatinib (10mg/kg) in ALK-amplified neuroblastoma PDX model (GR-NB4) mice (5 times per week for 2-3 weeks) leads to complete tumor regression. The combination therapy enhances apoptotic effects in vivo by activating the p53-BAX pathway[7]. Oral administration of RG7388 (25mg/kg/day) to tumor-bearing (KCNR or KP-N-YN cells) mice (once daily for 3 weeks), RG7388 significantly inhibits tumor growth as a monotherapy. In combination with the BCL-2 inhibitor Venetoclax (100mg/kg), RG7388 induces complete remission or partial tumor regression and significantly delays tumor recurrence[8].
References:
[1] Higgins B, Glenn K, Walz A, et al. Preclinical optimization of MDM2 antagonist scheduling for cancer treatment by using a model-based approach. Clin Cancer Res. 2014 Jul 15;20(14):3742-52.
[2] Ding Q, Zhang Z, Liu JJ, et al. Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development. J Med Chem. 2013 Jul 25;56(14):5979-83.
[3] Corbali MO, Eskazan AE. Idasanutlin as a new treatment option in improving the therapeutic odyssey of relapsed/refractory AML. Future Oncol. 2020 May;16(14):887-889.
[4] Mascarenhas J, Lu M, Kosiorek H, et al. Oral idasanutlin in patients with polycythemia vera. Blood. 2019 Aug 8;134(6):525-533.
[5] Johansson KB, Zimmerman MS, Dmytrenko IV, et al. Idasanutlin and navitoclax induce synergistic apoptotic cell death in T-cell acute lymphoblastic leukemia. Leukemia. 2023 Dec;37(12):2356-2366.
[6] Isermann T, Schneider KL, Wegwitz F, et al. Enhancement of colorectal cancer therapy through interruption of the HSF1-HSP90 axis by p53 activation or cell cycle inhibition. Cell Death Differ. 2025 Sep;32(9):1734-1749.
[7] Tucker ER, Jiménez I, Chen L, et al. Combination Therapies Targeting ALK-aberrant Neuroblastoma in Preclinical Models. Clin Cancer Res. 2023 Apr 3;29(7):1317-1331.
[8] Vernooij L, Bate-Eya LT, Alles LK, et al. High-Throughput Screening Identifies Idasanutlin as a Resensitizing Drug for Venetoclax-Resistant Neuroblastoma Cells. Mol Cancer Ther. 2021 Jun;20(6):1161-1172.
RG7388是一种具有口服活性的MDM2（IC50=6nM）拮抗剂，RG7388通过抑制MDM2-p53相互作用来激活p53通路[1-2]。RG7388可诱导细胞周期阻滞以减少肿瘤细胞增殖，RG7388可用于急性髓系白血病和实体瘤的相关研究[3-4]。
在体外，RG7388（0-90nM）处理TP53野生型的T细胞急性淋巴细胞白血病（T-ALL）细胞系MOLT-3 24-72小时，RG7388以p53依赖的方式诱导p53蛋白稳定和积累，上调促凋亡BH3域基因BAX和BBC3（PUMA）的表达，并引起caspase-3/7活性增加和细胞凋亡 [5]。RG7388（RG7388，1μM）处理结直肠癌（CRC）细胞系HCT116和RKO 24小时，RG7388可诱导细胞p53蛋白积累，与HSP90抑制剂Ganetespib（50nM）联用可协同降低细胞活力和汇合度，增加细胞死亡和PARP-1切割[6]。
在体内，RG7388（40-75mg/kg）与ALK抑制剂Lorlatinib（10mg/kg）联用口服处理ALK扩增型神经母细胞瘤PDX模型（GR-NB4）小鼠（每周5次，持续2-3周），RG7388可导致肿瘤完全消退，且联合治疗在体内通过激活p53-BAX通路增强凋亡效应[7]。RG7388（25mg/kg/day）口服处理荷瘤（KCNR或KP-N-YN细胞）小鼠（每日一次，持续3周），RG7388单药治疗显著抑制肿瘤生长，但与BCL-2抑制剂Venetoclax（100mg/kg）联用时可诱导完全缓解或部分肿瘤消退，并显著延缓肿瘤复发[8]。