Discovery Of Novel B-Raf Kinase Inhibitor With Potent Orally Anticancer Activity

Introduction: The B-Raf, one of serine/threonine kinase, is related to the Ras-Raf-MEK-ERK (MAPK) signal transduction. The signaling pathway plays a key role in cell survival, growth and proliferation. The B-Raf mutants are found in various cancer patients, such as melanoma, papillary thyroid, cisplatin-refractory testicular cancer, colorectal, ovarian, and prostate cancer. Especially, over 90% of detected mutations in B-Raf are a V600E which leads to constitutive kinase activity 500-fold greater than B-Raf wild type and correlates with increased malignancy and decreased response the chemotherapy. There are currently numerous efforts to develop therapeutic agents to target B-Raf or its downstream kinases. The first Raf inhibitor to enter clinical development was the multi-kinase inhibitor Nexavar (sorafenib tosylate), which is now approved for the treatment of patients with advanced renal cell carcinoma. However, the broad selectivity profile of this inhibitor makes it unsuitable for proof of concept evaluation of Raf kinase inhibition in tumors. Recently, more selective Raf inhibitors have been disclosed, and chemical inhibition of B-Raf enzymatic activity using these compounds can result in diminished proliferation and survival of tumor cells. However, very limited drug candidates with in vivo data have been published for B-Raf V600E . In this study, some of rational-designed compounds were synthesized and carried out the in vitro and in vivo studies to investigate more efficient B-Raf V600E inhibitors. Methods: About two hundreds of compounds were designed and synthesized. The in vitro assays and in vivo studies were performed to characterize the potential of B-Raf V600E inhibitors for solid tumors. Results: Compound UAI-201 had good inhibition effect in malignant cells expressing B-Raf V600E mutant type of cell-line (A375P GI 50 : 6nM / HT29 GI 50 : 5nM / COLO 205 GI 50 : 1nM), selectively. And the compound showed better tumor growth inhibition in xenograft mouse models (TGI(%): 61.87, 10mg/kg, PO, BID x 2weeks) compared with known inhibitors. In mechanism studies, the phosphorylation levels of MEK and ERK were effectively decreased by the UAI-201 compound in A375P cell-line. In addition, paradoxical effects were not detected compared with known compound. The compound had no toxicity in normal cell-line(HS-27 cell) and did not inhibit several CYP P450s. And also, UAI-201 showed good oral bioavailability with an acceptable clearance and half-life pharmacokinetic properties. Conclusions: The in vitro and in vivo studies of UAI-201 indicate that it is safe and efficacious, and suggests that it may good drug candidate for the preclinical study. Preclinical study our candidate, UAI-201, was started and the results will be disclosed in the near future. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1803. doi:1538-7445.AM2012-1803