Reference Detail

Contact

Missing content? – Request curation!

Request curation for specific Genes, Variants, or PubMed publications.

Have questions, comments, or suggestions? - Let us know!

Email us at : ckbsupport@jax.org

Ref Type Abstract
PMID
Authors 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
Title FCN-159: A novel, potent and selective oral inhibitor of MEK1/2 for the treatment of solid tumors
URL https://aacrjournals.org/cancerres/article/80/16_Supplement/1951/641598/Abstract-1951-FCN-159-A-novel-potent-and-selective
Abstract Text 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).

Filtering

  • Case insensitive filtering will display rows if any text in any cell matches the filter term
  • Use simple literal full or partial string matches
  • Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
  • Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

  • Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
FCN-159 FCN-159 3 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
FCN-159 FCN159|FCN 159 MEK1 Inhibitor 26 MEK2 Inhibitor 24 FCN-159 inhibits MAP2K1/2 (MEK1/2), potentially resulting in reduced proliferation and increased cell cycle arrest and apoptosis in tumor cells, and inhibition of tumor growth (Cancer Res 2020;80(16 Suppl):Abstract nr 1951).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NRAS mutant Advanced Solid Tumor predicted - sensitive FCN-159 Preclinical - Pdx Actionable In a preclinical study, FCN-159 inhibited tumor growth in patient-derived xenograft (PDX) models harboring NRAS mutations (Cancer Res 2020;80(16 Suppl):Abstract nr 1951). detail...