R162 is a potent inhibitor of glutamate dehydrogenase 1 (GDH1)[1]. R162 has good antitumor activity and does not cause significant toxicity to normal tissues[2].
In vitro, treatment of LKB1-deficient non-small cell lung cancer (NSCLC) cells (A549, H157, and H460 cells) with R162 (40μM) significantly induced apoptosis, which was reversed by α-KG treatment[3]. Treatment of SUM44 and LCCTam cells with R162 (10μM) for 4h significantly induced the production of intracellular ROS[4].
In vivo, treatment of A549 cell xenograft mice with R162 (20mg/kg) by intraperitoneal injection for 45 days significantly reduced tumor metastasis[3]. Treatment of U251 cell xenograft mice with R162 (30mg/kg) by intraperitoneal injection for 35 days significantly inhibited tumor growth in mice[5]. R162 (20mg/kg) was intraperitoneally injected into H1299 cell xenograft mice for 35 days, which significantly inhibited the tumor growth and mass of the mice and suppressed the activity of GDH1 in tumor tissues[6].
References:
[1] Bian Y, Hou W, Chen X, et al. Glutamate dehydrogenase as a promising target for hyperinsulinism hyperammonemia syndrome therapy[J]. Current Medicinal Chemistry, 2022, 29(15): 2652-2672.
[2] Ren J, Zhou J, Liu H, et al. Ultrasound (US)-activated redox dyshomeostasis therapy reinforced by immunogenic cell death (ICD) through a mitochondrial targeting liposomal nanosystem[J]. Theranostics, 2021, 11(19): 9470.
[3] Jin L, Chun J, Pan C, et al. The PLAG1-GDH1 axis promotes anoikis resistance and tumor metastasis through CamKK2-AMPK signaling in LKB1-deficient lung cancer[J]. Molecular cell, 2018, 69(1): 87-99. e7.
[4] Young T A, Bahnassy S, Abalum T C, et al. Glutamate Transport Proteins and Metabolic Enzymes are Poor Prognostic Factors in Invasive Lobular Carcinoma[J]. bioRxiv, 2024.
[5] Zhang J, Wang G, Mao Q, et al. Glutamate dehydrogenase (GDH) regulates bioenergetics and redox homeostasis in human glioma[J]. Oncotarget, 2016, 5.
[6] Jin L, Li D, Alesi G N, et al. Glutamate dehydrogenase 1 signals through antioxidant glutathione peroxidase 1 to regulate redox homeostasis and tumor growth[J]. Cancer cell, 2015, 27(2): 257-270.
R162是一种有效的谷氨酸脱氢酶1（GDH1）抑制剂[1]。R162具有良好的抗肿瘤活性，且不会对正常组织造成显著毒性[2]。
在体外，R162（40μM）处理LKB1缺陷的非小细胞肺癌（NSCLC）细胞（A549、H157和H460细胞），显著诱导了细胞凋亡，通过α-KG治疗可以逆转这一现象[3]。R162（10μM）处理SUM44和LCCTam细胞4h，显著诱导了细胞内ROS的产生[4]。
在体内，R162（20mg/kg）通过腹腔注射治疗A549细胞异种移植小鼠45天，显著减轻了肿瘤转移[3]。R162（30mg/kg）通过腹腔注射治疗U251细胞异种移植小鼠35天，显著抑制了小鼠体内肿瘤的生长[5]。R162（20mg/kg）通过腹腔注射治疗H1299细胞异种移植小鼠35天，显著抑制了小鼠的肿瘤生长和肿块，抑制了肿瘤组织中GDH1的活性[6]。