Cell lines

KRAS G13D and B-RAF G464V mutant MDA-MB-231T breast adenocarcinoma cell lines

Preparation method

The solubility of this compound in DMSO is >26.6 mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

0-10 nM

Applications

In the biochemical activity c-Raf/MEK1/ERK study, cobimetinib inhibited MEK1 activity with a IC50 value of 0.9 nM. Additionally, in MDA-MB-231T breast adenocarcinoma cells with KRAS G13D and B-RAF G464V mutant, cobimetinib was found to be able to inhibit MEK with the IC50 value of 0.2 nM.

Animal models

MDA-MB-231T mouse xenograft model

Dosage form

0.3-30 mg/kg, oral, qd

Application

In an MDA-MB-231T efficacy study, cobimetinib demonstrated tumor growth inhibition values of 60 and 93% at 1 and 3 mg/kg, respectively, and statistically significant tumor regression was observed at higher doses. Overall, predicted ED50 and ED90 values were 0.6 and around 3 mg/kg/day, respectively, in the latter case corresponding to peak circulating plasma levels in the range of 130 nM.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

Cobimetinib is a selective inhibitor of mitogen-activated protein kinase kinase (MEK) with IC50 value of 0.9 nM [1].
MEK is a kinase enzyme which selectively phosphorylates Ser/Thr and Tyr residues and involved in the mitogen-activated protein kinase (MAPK) signaling pathways that play an important role in regulation of cell proliferation, survival, differentiation, motility and angiogenesis [2].
In a KRAS G13D and B-RAF G464V mutant MDA-MB-231T breast adenocarcinoma cells, Cobimetinib inhibited MEK with IC50 value of 0.2 nM [1]. In pharmacokinetic-pharmacodynamic (PK-PD) model, Cobimetinib showed a sustained tumor pharmacodynamic response due to longer residence in tumor than in plasma [3].
In WM-266-4 xenograft mice, Cobimetinib decreased %pERK in tumor with IC50 values of 0.78 (WM-266-4) and 0.52 mM. Also, Cobimetinib (3.89 mM) increased IC50 value in WM-266-4 mice. In A375 xenograft mice, Cobimetinib (0.3-30 mg/kg) showed antitumor efficacy in a dose-dependent way. Cobimetinib is currently in phase I clinical trials as a potential antitumor agent [3].
References:
[1]. Rice KD, Aay N, Anand NK, et al. Novel Carboxamide-Based Allosteric MEK Inhibitors: Discovery and Optimization Efforts toward XL518 (GDC-0973). ACS Med Chem Lett, 2012, 3(5): 416-421.
[2]. Akinleye A, Furqan M, Mukhi N, et al. MEK and the inhibitors: from bench to bedside. J Hematol Oncol, 2013, 6: 27.
[3]. Wong H, Vernillet L, Peterson A, et al. Bridging the gap between preclinical and clinical studies using pharmacokinetic-pharmacodynamic modeling: an analysis of GDC-0973, a MEK inhibitor. Clin Cancer Res, 2012, 18(11): 3090-3099.