Cobimetinib-d₄ hydrochloride  (Synonyms: GDC-0973-d₄ hydrochloride; XL518-d₄ hydrochloride)

Cobimetinib-d₄ hydrochloride is deuterated labeled Cobimetinib (HY-13064). Cobimetinib (GDC-0973, RG7420) is a potent, selective and oral MEK1 inhibitor with an IC₅₀ of 4.2 nM for MEK1.

Stable heavy isotopes of hydrogen, carbon, and other elements have been incorporated into drug molecules, largely as tracers for quantitation during the drug development process. Deuteration has gained attention because of its potential to affect the pharmacokinetic and metabolic profiles of drugs^[1].
The EC₅₀ values of Cobimetinib (GDC-0973) for 888MEL and A2058 cells are 0.2 μM, 10 μM, respectivelly. Melanoma cells are treated with EC₅₀ concentration of MEK and PI3K inhibitors for 24 hours (888MEL: 0.05 μM GDC-0973, 2.5 μM GDC-0941; A2058: 2.5 μM GDC-0973, 2.5 μM GDC-0941)^[2]. Mitochondrial OXPHOS limits cell death induced by cobimetinib (100 nM) in melanoma with constitutive MAPK activation in A375 cells^[5].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

In the NCI-H2122 KRASG12C mutant non-small cell lung carcinoma (NSCLC) xenograft model, treatment with up to 5 mg/kg Cobimetinib (GDC-0973) lead to moderate TGI and at 10 mg/kg approaches tumor stasis^[2].
GDC-0973 and GDC-0941 are administered to A2058 tumor-bearing mice daily (QD) or every third day (Q3D) either as single agents or in combination. The population rate constants associated with tumor growth inhibition for GDC-0973 and GDC-0941 are 0.00102 and 0000651 μM^-1 h^-1, respectively^[3].
Following single doses of GDC-0973 (1, 3, or 10 mg/kg, p.o.) estimated in vivo IC₅₀ values of %pERK decrease based on tumor concentrations in xenograft mice are 0.78 (WM-266-4) and 0.52 μM (A375)^[4].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

571.80

C₂₁H₁₈D₄ClF₃IN₃O₂

OC1(C([2H])(N(C(C2=C(NC3=C(F)C=C(I)C=C3)C(F)=C(F)C=C2)=O)C1([2H])[2H])[2H])[C@H]4NCCCC4.Cl

Room temperature in continental US; may vary elsewhere.

Please store the product under the recommended conditions in the Certificate of Analysis.

• [1]. Russak EM, et al. Impact of Deuterium Substitution on the Pharmacokinetics of Pharmaceuticals. Ann Pharmacother. 2019 Feb;53(2):211-216.  [Content Brief]

  [2]. Hoeflich KP, et al. Intermittent administration of MEK inhibitor GDC-0973 plus PI3K inhibitor GDC-0941 triggers robust apoptosis and tumor growth inhibition. Cancer Res. 2012 Jan 1;72(1):210-9.  [Content Brief]

  [3]. Corazao-Rozas P, et al. Mitochondrial oxidative phosphorylation controls cancer cell's life and death decisions upon exposure to MAPK inhibitors. Oncotarget. 2016 Feb 29. doi: 10.18632/oncotarget.7790.  [Content Brief]

  [4]. Choo EF, 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. Cancer Chemother Pharmacol. 2013 Jan;71(1):133-43.  [Content Brief]

  [5]. Wong H, 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 Jun 1;18(11):3090-9.  [Content Brief]