Cobimetinib is a selective MEK1/2 inhibitor that exerts anti-tumor effects by blocking the RAS/RAF/MEK/ERK signaling pathway. It is mainly used to treat BRAFV600 mutation positive unresectable or metastatic melanoma. Its core functions include inhibiting tumor cell proliferation, inducing apoptosis, and enhancing immune response. It is often used in combination with BRAF inhibitors to delay the development of drug resistance.

1. Core pharmacological effects

(1) Signal pathway inhibition: Specifically binding to the ATP binding site of MEK1/2, blocking ERK phosphorylation and inhibiting the abnormally activated MAPK pathway, which plays a key driving role in BRAF mutant tumors.

(2) Cell cycle arrest: By downregulating the expression of cyclin D1, tumor cells are arrested in the G1 phase, inhibiting DNA replication and mitosis.

(3) Proapoptotic effect: Upregulation of pro apoptotic protein BIM expression while inhibition of anti apoptotic protein MCL-1, dual mechanism induces programmed cell death in tumor cells.

2 Clinical treatment efficacy

(1) Melanoma treatment: The combination with Vimafenib significantly prolongs progression free survival (PFS) in BRAFV600 mutation patients, with an objective response rate of 68% and a median PFS of 12.3 months.

(2) Drug resistance management: By vertically inhibiting the upstream and downstream of the MAPK pathway (BRAF+MEK), reducing pathway reactivation caused by monotherapy and prolonging the duration of drug efficacy.

(3) Immune regulation: Reduce the secretion of immunosuppressive factors such as IL-6 and VEGF in the tumor microenvironment, enhance T cell infiltration and activity, and potentially improve the efficacy of immunotherapy.

3 Special mechanisms of action

(1) Selective inhibition: The inhibitory activity against MEK1/2 is more than 100 times higher than other kinases, reducing adverse reactions caused by off target effects.

(2) Metabolic stability: Mainly metabolized by CYP3A4, with a half-life of about 44 hours, supporting a once daily dosing regimen and improving patient compliance.

(3) Organizational distribution: The concentration in tumor tissue can reach 5 times that of plasma concentration, demonstrating good targeted accumulation characteristics.