Cobimetinib

Cobimetinib is a potent and selective inhibitor of MEK1 with an IC₅₀ value of 0.9nM^[1]. Cobimetinib can induce a decrease in the activity of phosphorylated ERK, leading to endoplasmic reticulum stress response and promoting cell death^[2]. Cobimetinib has been widely used in xenograft tumor models to inhibit tumor growth^[3].

In vitro, Cobimetinib treatment for 96 hours significantly inhibited the viability of LS174T, RW7213 and RW2982 cells, with IC₅₀ values of 0.28μM, 0.23μM and 0.44μM respectively^[4]. Treatment of HCT116 cells with 1µM Cobimetinib for 24 hours led to a decrease in the expression levels of cyclin D1 and cyclin E, an increase in the expression level of p21, and induced G1 phase arrest^[5]. Treatment of IMR-32 cells with 1µM Cobimetinib for 24 hours induced PARP cleavage and cell apoptosis^[6].

In vivo, Cobimetinib treatment via oral administration at a dose of 1mg/kg/day for 21 consecutive days significantly inhibited tumor growth, tumor angiogenesis, and ERK signal transduction in the xenograft mouse model of hepatocellular carcinoma^[7]. The combined use of Cobimetinib (10mg/kg/day; p.o.) and venetoclax (100mg/kg/day; p.o.) for 28 consecutive days can reduce the leukemia burden in the mouse model of acute myeloid leukemia and prolong the survival time of the mice^[8].

References:
[1] Rice K D, Aay N, Anand N K, et al. Novel carboxamide-based allosteric MEK inhibitors: discovery and optimization efforts toward XL518 (GDC-0973)[J]. ACS medicinal chemistry letters, 2012, 3(5): 416-421.
[2] Corazao-Rozas P, Guerreschi P, André F, et al. Mitochondrial oxidative phosphorylation controls cancer cell's life and death decisions upon exposure to MAPK inhibitors[J]. Oncotarget, 2016, 7(26): 39473.
[3] Choo E F, Ng C M, Berry L, et al. PK-PD modeling of combination efficacy effect from administration of the MEK inhibitor GDC-0973 and PI3K inhibitor GDC-0941 in A2058 xenografts[J]. Cancer chemotherapy and pharmacology, 2013, 71(1): 133-143.
[4] Kuracha M R, Thomas P, Loggie B W, et al. Bilateral blockade of MEK-and PI3K-mediated pathways downstream of mutant KRAS as a treatment approach for peritoneal mucinous malignancies[J]. PLoS One, 2017, 12(6): e0179510.
[5] Gong S, Xu D, Zhu J, et al. Efficacy of the MEK inhibitor cobimetinib and its potential application to colorectal cancer cells[J]. Cellular Physiology and Biochemistry, 2018, 47(2): 680-693.
[6] Singh A, Ruan Y, Tippett T, et al. Targeted inhibition of MEK1 by cobimetinib leads to differentiation and apoptosis in neuroblastoma cells[J]. Journal of Experimental & Clinical Cancer Research, 2015, 34(1): 104.
[7] Tong X, Wang Q, Wu D, et al. MEK inhibition by cobimetinib suppresses hepatocellular carcinoma and angiogenesis in vitro and in vivo[J]. Biochemical and Biophysical Research Communications, 2020, 523(1): 147-152.
[8] Han L, Zhang Q, Dail M, et al. Concomitant targeting of BCL2 with venetoclax and MAPK signaling with cobimetinib in acute myeloid leukemia models[J]. Haematologica, 2019, 105(3): 697.

Cobimetinib是一种强效、选择性的MEK1抑制剂，IC₅₀值为0.9nM^[1]。Cobimetinib通过降低磷酸化ERK的活性，诱导内质网应激反应，进而促进细胞死亡^[2]。Cobimetinib已在多种移植瘤模型中广泛应用于抑制肿瘤生长^[3]。

在体外，Cobimetinib处理96小时能显著抑制LS174T、RW7213和RW2982细胞的活力，IC₅₀值分别为0.28μM、0.23μM和0.44μM^[4]。使用1μM的Cobimetinib处理HCT116细胞24小时，可降低细胞周期蛋白D1和E的表达水平，提高p21表达，并诱导G1期周期阻滞^[5]。用1μM的Cobimetinib处理IMR-32细胞24小时，能诱导PARP裂解和细胞凋亡^[6]。

在体内，连续21天每日口服1mg/kg/day剂量的Cobimetinib，可显著抑制肝癌移植瘤小鼠模型的肿瘤生长、肿瘤血管生成及ERK信号转导^[7]。联合使用Cobimetinib(10mg/kg/day; p.o.)与venetoclax (100mg/kg/day; p.o.)连续治疗28天，能减轻急性髓系白血病小鼠模型的肿瘤负荷，并延长小鼠生存时间^[8]。