生物活性

• 描述The MAPK/ERK (mitogen-activated protein kinase/extracellular signal-regulated kinase) kinase (MEK) signalling cascade is a key regulator of cellular proliferation, differentiation and survival downstream of RAS activation. Upregulation of this pathway occurs in a large fraction of tumours. GDC-0623 is a potent, ATP-uncompetitive inhibitor of MEK1 with K_i value of 0.13 nM^[3]. GDC-0623 up-regulated BIM (Bcl-2 Interacting Mediator of cell death) expression to a greater extent versus other MEK inhibitors in isogenic KRAS HCT116 and mutant KRAS SW620 colon cancer cells^[1]. In KRAS-mutant cells, block of pMEK (phosphorylated MEK) accumulation caused by GDC-0623 (range: 0.00045–0.33 μM in threefold increments) resulted in more effective inhibition of pERK. MEK phosphorylation was blocked by CRAF and BRAF (V600E) in vitro in the presence of 0.01, 0.1 and 1 μM GDC-0623. In KRAS-mutant cells GDC-0623 at 0.1, 1 and 10 μM induced dimerization of MEK with both BRAF and CRAF. The average plasma concentration of GDC-0973 over 24 hours at its maximum tolerated dose (MTD) is 0.63 μM for GDC-0623. In KRAS-mutant xenograft model, superior antitumour activity was observed with GDC-0623 at its MTD^[3].
• 作用机制GDC-0623 forms a strong hydrogen-bond interaction with S212 in MEK^[3].