Cobimetinibは有力で選択的なMEK1の阻害剤であり、IC50値は0.9nMである[1]。Cobimetinibはリン酸化のERKの活性を減らし、小胞体ストレス応答を起こし、細胞死を促進できる[2]。Cobimetinibは異種移植腫瘍モデルに広く使われ、腫瘍の成長を阻害してきている[3]。
体外で、96時間のCobimetinibの処理は、LS174T、RW7213とRW2982細胞の生存率を著しく阻害し、IC50値はそれぞれ0.28μM、0.23μMと0.44μMであった[4]。1µM CobimetinibでHCT116細胞を24時間処理した結果、サイクリンD1とサイクリンEの発見レベルを減らし、p21の発見レベルを増やし、G1期停止を誘発した[5]。1µM CobimetinibでIMR-32細胞を24時間処理した結果、PARP切断と細胞アポトーシスを誘発した[6]。
体内で、1mg/kg/日のCobimetinibを21日間連続経口投与した結果、肝細胞癌異種移植マウスモデルで、腫瘍成長、腫瘍の血管新生、ERKシグナルの伝達を著しく阻害した[7]。Cobimetinib (10mg/kg/日；経口投与)とvenetoclax (100mg/kg/日；経口投与)を併用して28日間連続的に投与した結果、急性骨髄白血病のマウスモデルで、白血病の負担量を減らし、マウスの生存期間を延ばせる[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.