MEK1/2 (Mitogen-activated protein kinase kinase 1/2) is a key member in the RAS/RAF/MEK/ERK signaling pathway. The MEK pathway is found ubiquitously in tissues and regulates multiple cellular processes including proliferation, differentiation, migration, survival and angiogenesis. Dysregulation of MEK pathway through mutations in BRAF, KRAS and NRAS is frequently found in many types of cancers, such as melanoma, non-small cell lung cancer (NSCLC), prostate cancer and breast cancer, acute myeloid leukemia and acute lymphoblastic leukemia (ALL). MEK inhibitors inhibit cell proliferation, induce cell cycle arrest, as well as cell apoptosis in cancer cells, making MEK inhibition an effective anti-cancer strategy. Here we introduce FCN-159, a novel, selective and orally active inhibitor of MEK1/2. FCN-159 demonstrated selective kinase activities against MEK1 and MEK2. FCN-159 exhibited remarkable potency against the cell proliferation of a panel of human cancer cell lines with RAS/RAF mutations while sparing normal or cancer cell lines expressing wild type RAS/RAF, indicating highly selective inhibition against RAS/RAF/MEK signaling pathway. In human colon cancer cells, FCN-159 dose-dependently inhibited the phosphorylation of MEK downstream effector ERK and induced cell cycle arrest as well as cell apoptosis. FCN-159 showed significant and dose-dependent anti-tumor activities in a variety of human tumor xenograft models, derived from colon cancer (HT-29 and Colo205), melanoma (A375), NSCLC (Calu-6) and AML (HL-60). In addition, FCN-159 potently inhibited tumor growth in two patient-derived xenograft (PDX) models bearing NRAS mutation. The in vivo anti-tumor activity of FCN-159 was comparable to or stronger than FDA-approved MEK inhibitor trametinib. In non-clinical studies, FCN-159 exhibited excellent pharmacokinetic (PK) and safety properties. In particular, FCN-159 had longer T1/2 and higher dose-normalized AUC in both rats and dogs, compared with trametinib. Overall, FCN-159 exhibits great potential as a clinically-useful MEK inhibitor, as seen in its marked in vitro and in vivo anti-tumor efficacy, improved PK properties and good safety profiles. FCN-159 can be a novel and effective targeted monotherapy and potentially in combination to treat patients with advanced solid tumors. A Phase I clinical trial of FCN-159 is ongoing in China to treat patients with NRAS-aberrant (Ia) and NRAS-mutant (Ib) advanced melanoma (NCT03932253).

Citation Format: Shu Lin, Xingdong Zhao, Zuwen Zhou, Haohan Tan, Ling Chen, Rui Tan, Weipeng Zhang, Lihua Jiang, Li Linghu, Jing Sun, Jiashu Zhou, Te Li, Yunlong Song, Weibo Wang. FCN-159: A novel, potent and selective oral inhibitor of MEK1/2 for the treatment of solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1951.