title: Preclinical in vivo evaluation of efficacy, pharmacokinetics, and pharmacodynamics of a novel MEK1/2 kinase inhibitor RO5068760 in multiple tumor models.
abstract: Targeting the Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway represents a promising anticancer strategy. Recently, we have reported a novel class of potent and selective non-ATP-competitive MEK1/2 inhibitors with a unique structure and mechanism of action. RO5068760 is a representative of this class showing significant efficacy in a broad spectrum of tumors with aberrant mitogen-activated protein kinase pathway activation. To understand the relationship between systemic exposures and target (MEK1/2) inhibition as well as tumor growth inhibition, the current study presents a detailed in vivo characterization of efficacy, pharmacokinetics, and pharmacodynamics of RO5068760 in multiple xenograft tumor models. For inhibition of MEK1/2 as measured by the phosphorylated ERK levels, the estimated EC(50)s in plasma were 1.36 micromol/L (880 ng/mL) and 3.35 micromol/L (2168 ng/mL) in LOX melanoma and HT-29 colorectal cancer models, respectively. A similar EC(50) (1.41 micromol/L or 915 ng/mL) was observed in monkey peripheral blood lymphocytes. To achieve tumor growth inhibition (>or=90%), an average plasma drug concentration of 0.65 or 5.23 micromol/L was required in B-RafV600E or K-Ras mutant tumor models, respectively, which were remarkably similar to the IC(90) values (0.64 or 4.1 micromol/L) determined in vitro for cellular growth inhibition. With equivalent in vivo systemic exposures, RO5068760 showed superior efficacy in tumors harboring B-RafV600E mutation. The plasma concentration time profiles indicate that constant p-ERK suppression (>50%) may not be required for optimal efficacy, especially in highly responsive tumors. This study may facilitate future clinical trial design in using biochemical markers for early proof of mechanism and in selecting the right patients and optimal dose regimen.
authors.affiliation: Discovery Oncology, Hoffmann-La Roche, Inc., Nutley, New Jersey 07110, USA.
authors.forename: Sherif
authors.initials: S
authors.lastname: Daouti
authors.forename: Brian
authors.initials: B
authors.lastname: Higgins
authors.forename: Kenneth
authors.initials: K
authors.lastname: Kolinsky
authors.forename: Kathryn
authors.initials: K
authors.lastname: Packman
authors.forename: Huisheng
authors.initials: H
authors.lastname: Wang
authors.forename: Christine
authors.initials: C
authors.lastname: Rizzo
authors.forename: John
authors.initials: J
authors.lastname: Moliterni
authors.forename: Nicholas
authors.initials: N
authors.lastname: Huby
authors.forename: Nader
authors.initials: N
authors.lastname: Fotouhi
authors.forename: Mei
authors.initials: M
authors.lastname: Liu
authors.forename: Petra
authors.initials: P
authors.lastname: Goelzer
authors.forename: Harpreet K
authors.initials: HK
authors.lastname: Sandhu
authors.forename: Jia Kui
authors.initials: JK
authors.lastname: Li
authors.forename: Aruna
authors.initials: A
authors.lastname: Railkar
authors.forename: David
authors.initials: D
authors.lastname: Heimbrook
authors.forename: Huifeng
authors.initials: H
authors.lastname: Niu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D048289:Imidazolidines / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors*; D008252:Macaca fascicularis; D051379:Mice; D008819:Mice, Nude; D010654:Phenylbutyrates / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C547875:2-(4-(4-(2,3-dihydroxy-propoxy)phenyl)-2,5-dioxo-imidazolidin-1-yl)-N-(2-fluoro-4-iodo-phenyl)-3-phenylbutyramide; D048289:Imidazolidines; D010654:Phenylbutyrates; D047428:Protein Kinase Inhibitors; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2