Ikumi Hyoudoh

Synthesis and structure-activity relationships of novel benzofuran farnesyltransferase inhibitors.

A series of benzofuran-based farnesyltransferase inhibitors have been designed and synthesized as antitumor agents. Among them, 11f showed the most potent enzyme inhibitory activity (IC(50)=1.1nM) and antitumor activity in human cancer xenografts in mice.

Abstract 2789: Discovery of a novel specific MEK and Raf inhibitor, CH5126766 (RO5126766), hit to lead study of a unique scaffold for kinase inhibitor to a clinical compound

Background: Among tumor signaling pathways, the most frequently dysregulated in human cancer is Ras-Raf-MEK axis, and therefore allosteric MEK inhibitors and ATP competitive Raf inhibitors are being tested in clinical trials. However, these inhibitors result in marked activation of upstream signal of MEK in tumor cells, especially with mutant K-ras. This feedback activation or activation of Raf would attenuate the anticancer effects of these inhibitors. One of the strategies to prevent this attenuation will be blocking upstream signal concurrent with MEK inhibition. To validate the hypothesis, we executed a hit to lead study of our HTS hit showing MEK/Raf dual inhibition. Methods and Results: To increase direct MEK inhibitory activity (by binding to MEK) of the HTS hit coumarin compound and indirect Raf inhibitory activity (by enhancement of the binding between B-Raf /C-Raf and MEK1), introduction of a sulfamide group afforded the best result, compared with similar functional groups such as urea, amide and sulfonamide. Fluorine-scan (C-H/C-F substitutions) and nitrogen-scan (CH/N substitutions) worked efficient to increase both MEK and Raf inhibitory activities and optimize physicochemical properties (water solubility, hERG inhibition, CYP inhibitions etc). These three key transformations afforded CH5126766, which has MEK1 (IC50 = 160 nM) and B-Raf (IC50 = 19 nM) inhibitions and excellent PK profiles (mouse BA 93%, CL 1.1 mL/min/kg, rat BA 66%, CL 0.7 mL/min/kg, monkey BA 82%, CL 0.1 mL/min/kg). The compound showed potent antitumor activity in human cancer xenograft model (HCT116) by once daily oral administration (128% of tumor growth inhibition at a 1 mg/kg dose). Conclusion: SAR study of our novel type molecule (MEK and Raf dual inhibitor) affords identification of CH5126766. It showed strong antitumor efficacy in vivo, good PK in three animal species and good safety profiles. Thus, CH5126766 is now under clinical investigation with solid tumor patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2789. doi:10.1158/1538-7445.AM2011-2789