Reference Detail

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer Research	80	16_suppl	August 15, 2020

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...