Rheb inhibitor NR1 is a small molecule that inhibits the monomeric protein Rheb with an IC50 value of 2.1μM [1]. Rheb inhibitor NR1 targets the switch II domain of Rheb1 via hydrophobic interactions, specifically inhibiting mTORC1 activity [2]. Rheb inhibitor NR1 has been widely used to promote cell survival under conditions of glucose deprivation [3].
In vitro, Treatment of PK-15 cells with 30μM Rheb inhibitor NR1 for 12 hours significantly reduced the replication of foot-and-mouth disease virus (FMDV) in the cells[4]. Treatment with Rheb inhibitor NR1 (10μM) for 24 hours significantly inhibited the expression of OTUD4 and GPX4 in HEK293T cells[5].
In vivo, Rheb inhibitor NR1 treatment (1mg/kg; three times a week; i.p.) combined with NSC23766 for 2 weeks attenuated hearing dysfunction in Tnfaip8l2−/− mice and improved the disordered arrangement of stereocilia[6].
References:
[1] Mahoney S J, Narayan S, Molz L, et al. A small molecule inhibitor of Rheb selectively targets mTORC1 signaling[J]. Nature communications, 2018, 9(1): 548.
[2] Rahman M, Nguyen T M, Lee G J, et al. Unraveling the role of ras homolog enriched in brain (Rheb1 and Rheb2): bridging neuronal dynamics and cancer pathogenesis through mechanistic target of rapamycin signaling[J]. International Journal of Molecular Sciences, 2024, 25(3): 1489.
[3] Li M, Huang W, Zhang Y, et al. Glucose deprivation triggers DCAF1-mediated inactivation of Rheb-mTORC1 and promotes cancer cell survival[J]. Cell Death & Disease, 2024, 15(6): 409.
[4] Liu H, Zhu Z, Xue Q, et al. Picornavirus infection enhances aspartate by the SLC38A8 transporter to promote viral replication[J]. PLoS pathogens, 2023, 19(2): e1011126.
[5] Chen J, Huang C, Mei J, et al. OTUD4 inhibits ferroptosis by stabilizing GPX4 and suppressing autophagic degradation to promote tumor progression[J]. Cell Reports, 2025, 44(5).
[6] Li W, Li Y, Wang M, et al. TNFAIP8L2 maintains hair cell function and regulates age-related hearing loss via mTORC1 signaling[J]. Molecular Therapy, 2025, 33(7): 3036-3055.
Rheb inhibitor NR1是一种小分子，可抑制单体蛋白Rheb，IC50值为2.1μM[1]。Rheb inhibitor NR1通过疏水相互作用靶向Rheb1的开关II结构域，特异性抑制mTORC1活性[2]。Rheb inhibitor NR1已被广泛用于在葡萄糖剥夺条件下促进细胞存活[3]。
在体外，用30μM的Rheb inhibitor NR1处理PK-15细胞12小时，可显著减少口蹄疫病毒（FMDV）在细胞中的复制[4]。用Rheb inhibitor NR1（10μM）处理HEK293T细胞24小时，显著抑制了OTUD4和GPX4的表达[5]。
在体内，Rheb inhibitor NR1（1mg/kg；每周三次；腹腔注射）联合NSC23766治疗2周，可减轻Tnfaip8l2−/−小鼠的听力功能障碍，并改善静纤毛的紊乱排列[6]。