Molecule

Description

Cancer

Description

SB590885 is a potent B-Raf inhibitor with K_i of 0.16 nM.

Targets

IC₅₀

In Vitro

SB590885 displays significant selectivity for B-Raf over c-Raf with K_i of 0.16 nM over 1.72 nM. SB-590885 is a more potent inhibitor than the previously described Raf/VEGFR kinase inhibitor BAY 439006 (K_i = 38 nM for mutant B-Raf, 6 nM for c-Raf). SB590885 displays potent selectivity over 46 other kinases. Unlike the multi-kinase inhibitor BAY43-9006, SB590885 stabilizes the oncogenic B-Raf kinase domain in an active configuration. In Colo205, HT29, A375P, SKMEL28, and MALME-3M cells expressing oncogenic B-RafV600E, SB590885 treatment potently inhibits ERK phosphorylation with EC50 of 28 nM, 58 nM, 290 nM, 58 nM, and 190 nM, respectively, and consistently, inhibits the proliferation with EC50 of 0.1 μM, 0.87 μM, 0.37 μM, 0.12 μM, and 0.15 μM, respectively. SB590885 decreases anchorage-independent growth of melanoma cell lines in a BRAF mutant-selective manner. ^[1] SB590885 displays high affinity for B-Raf with Kd of 0.3 nM. ^[2] Most of the melanoma cell lines that harbor the BRAF V600E mutation and lack CDK4 mutations (451Lu, WM35, and WM983) are highly sensitive to SB590885 with IC50 of <1 μm.="" increased="" levels="" of="" cyclin="" d1="" resulting="" from="" genomic="" amplification="" mediate="" sb590885="" resistance="" in="" b-raf="" v600e-mutated="" melanomas.="">^[3]

In Vivo

Administration of SB590885 potently decreases tumorigenesis in murine xenografts established from mutant B-Raf-expressing A375P melanoma cells, and modestly inhibits tumor growth. ^[1]

Clinical Trials

Features

SB590885 displays significant selectivity for B-Raf over c-Raf.

Cell Lines

Colo205, HT29, A375P, SKMEL28, and MALME-3M

Concentrations

Dissolved in DMSO, final concentrations ~10 μM

Incubation Time

72 hours

Methods

Cells are treated with increasing concentrations of SB590885 and incubated for 72 hours. Viable cells are quantified using CellTiter-Glo reagent and luminescence detection on a Victor 2V plate reader. Cells are prepared for cell cycle analysis on a Becton Dickinson FACScan. Data is acquired and analyzed using CellQuest v3.3 software.

Animal Models

Female nude mice injected s.c. with of A375P cells

Formulation

Dissolved in vehicle [2% N,N-dimethylacetamide, 2% Cremophor EL, and 96% acidified water (pH f4–5)]

Doses

50 mg/kg/day

Administration

Injection i.p.