Nicholas John Silvester Huby

Peptidomimetic compounds that inhibit antigen presentation by autoimmune disease-associated class II major histocompatibility molecules

We have identified a heptapeptide with high affinity to rheumatoid arthritis–associated class II major histocompatibility (MHC) molecules. Using a model of its interaction with the class II binding site, a variety of mimetic substitutions were introduced into the peptide. Several unnatural amino acids and dipeptide mimetics were found to be appropriate substituents and could be combined into compounds with binding affinities comparable to that of the original peptide. Compounds were designed that were several hundred-fold to more than a thousand-fold more potent than the original peptide in inhibiting T-cell responses to processed protein antigens presented by the target MHC molecules. Peptidomimetic compounds of this type could find therapeutic use as MHC-selective antagonists of antigen presentation in the treatment of autoimmune diseases.

Preclinical In vivo Evaluation of Efficacy, Pharmacokinetics, and Pharmacodynamics of a Novel MEK1/2 Kinase Inhibitor RO5068760 in Multiple Tumor Models

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 EC50s in plasma were 1.36 μmol/L (880 ng/mL) and 3.35 μmol/L (2168 ng/mL) in LOX melanoma and HT-29 colorectal cancer models, respectively. A similar EC50 (1.41 μmol/L or 915 ng/mL) was observed in monkey peripheral blood lymphocytes. To achieve tumor growth inhibition (≥90%), an average plasma drug concentration of 0.65 or 5.23 μmol/L was required in B-RafV600E or K-Ras mutant tumor models, respectively, which were remarkably similar to the IC90 values (0.64 or 4.1 μmol/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. Mol Cancer Ther; 9(1); 134–44

Characterization of a Novel Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor with a Unique Mechanism of Action for Cancer Therapy

The mitogen-activated protein kinase (MAPK) signal transduction pathway plays a central role in regulating tumor cell growth, survival, differentiation, and angiogenesis. The key components of the Ras/Raf/MEK/ERK signal module are frequently altered in human cancers. Targeting this pathway represents a promising anticancer strategy. Small molecule inhibitors targeting MEK1/2 have shown promise in the clinic; however, ultimate clinical proof-of-concept remains elusive. Here, we report a potent and highly selective non-ATP-competitive MEK1/2 inhibitor, RO4927350, with a novel chemical structure and unique mechanism of action. It selectively blocks the MAPK pathway signaling both in vitro and in vivo, which results in significant antitumor efficacy in a broad spectrum of tumor models. Compared with previously reported MEK inhibitors, RO4927350 inhibits not only ERK1/2 but also MEK1/2 phosphorylation. In cancer cells, high basal levels of phospho-MEK1/2 rather than phospho-ERK1/2 seem to correlate with greater sensitivity to RO4927350. Furthermore, RO4927350 prevents a feedback increase in MEK phosphorylation, which has been observed with other MEK inhibitors. We show that B-Raf rather than C-Raf plays a critical role in the feedback regulation. The unique MAPK signaling blockade mediated by RO4927350 in cancer may reduce the risk of developing drug resistance. Thus, RO4927350 represents a novel therapeutic modality in cancers with aberrant MAPK pathway activation.

N-Cycloalkanoyl-L-phenylalanine derivatives as VCAM/VLA-4 antagonists.

A systematic structure-activity relationship investigation of the lead compound 1 resulted the identification of several N-[(substituted alkyl)cycloalkanoyl]-4-[((2,6-dichlorophenyl)carbonyl)amino]-L-phenylalanine derivatives as potent VCAM/VLA-4 antagonists. The data are consistent with a model of these compounds in which these alkanoylphenylalanines reside in a compact gauche (-) bioactive conformation.

Abstract A247: Preclinical antitumor activity of the MEK inhibitor RO5068760 in human tumor xenograft models

RO5068760 is a representative member of a new class of potent, highly selective, non‐adenosine triphosphate (ATP) competitive MEK inhibitors. In tumor cells, RO5068760 selectively blocked MAPK pathway signaling by inhibiting the phosphorylation of both ERK1/2 and MEK1/2. Human tumor cell lines bearing MAPK pathway gene mutations such as B‐Raf and Ras were preferentially sensitive to RO5068760 treatment in vitro. When administered orally to tumor‐bearing mice, RO5068760 demonstrated dose‐dependent anti‐tumor activity in a variety of human xenograft models including melanoma, colorectal, pancreatic, and non‐small cell lung cancer (NSCLC). RO5068760 elicited statistically significant tumor growth inhibition in all models tested when administered once daily (qd) or twice daily (bid). At an optimal dose of 100 mg/kg bid, partial regressions (PRs) were demonstrated in 3/4 tumor models, and complete regressions (CRs) in 1/4 models tested. Antitumor efficacy was proportional with drug plasma exposure and inhibition of ERK1/2 phosphorylation, with slightly better efficacy observed with bid vs qd administration in the MiaPaCa‐2 (pancreatic) and H460a (NSCLC) models. In the Lox melanoma model, animals treated at doses as low as 12.5 mg/kg bid exhibited CRs, which further supported the observation made in vitro that tumor cells bearing B‐Raf mutations had the greatest sensitivity to RO5068760. Combination treatment of mice bearing MiaPaca‐2 xenografts with 2/3 optimal doses (ODs) of RO5068760 and Gemcitabine significantly enhanced the antitumor activity as compared to either monotherapy. These results suggest that RO5068760 is a promising candidate for further development in the treatment of human cancers with aberrant MAPK pathway activation. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A247.