Biological Activity of PLX-4032 (RG7204, Vemurafenib, Zelboraf)

[kinsxu]

A p.o.-bioavailable ALK(Alkylphospholipids),inhibits Akt activation. Targeting cellular membranes, perifosine modulates membrane permeability, membrane lipid composition, phospholipid metabolism, and mitogenic signal transduction, resulting in cell differentiation and inhibition of cell growth. This agent also inhibits the anti-apoptotic mitogen-activated protein kinase (MAPK) pathway and modulates the balance between the MAPK and pro-apoptotic stress-activated protein kinase (SAPK/JNK) pathways, thereby inducing apoptosis. Perifosine has a lower gastrointestinal toxicity profile than the related agent miltefosine. Immortalized keratinocytes (HaCaT) as well as head and neck squamous carcinoma cells were sensitive to the antiproliferative properties of perifosine with an IC50 of 0.6–8.9 μM.

[kinsxu]

Linifanib (ABT-869) is a structurally novel, potent RTK and VEGF and PDGF receptor families inhibitor with IC50 of 0.2, 2, 4, and 7 nM for human endothelial cells, PDGFR-β, KDR, and CSF-1R, respectively. It has much less activity (IC50s > 1 μM) against unrelated RTKs, soluble tyrosine kinases, or serine/threonine kinases. In vivo ABT-869 is effective orally in the mechanism-based murine models of VEGF-induced uterine edema (ED50 = 0.5 mg/kg) and corneal angiogenesis ( >50%inhibition, 15 mg/kg ).