Demonstration of a Genetic Therapeutic Index for Tumors Expressing Oncogenic BRAF by the Kinase Inhibitor SB-590885

Abstract

Oncogenic BRAF alleles are both necessary and sufficient for cellular transformation, suggesting that chemical inhibition of the activated mutant protein kinase may reverse the tumor phenotype. Here, we report the characterization of SB-590885, a novel triarylimidazole that selectively inhibits Raf kinases with more potency towards B-Raf than c-Raf. Crystallographic analysis revealed that SB-590885 stabilizes the oncogenic B-Raf kinase domain in an active configuration, which is distinct from the previously reported mechanism of action of the multi-kinase inhibitor, BAY43-9006. Malignant cells expressing oncogenic B-Raf show selective inhibition of mitogen-activated protein kinase activation, proliferation, transformation, and tumorigenicity when exposed to SB-590885, whereas other cancer cell lines and normal cells display variable sensitivities or resistance to similar treatment. These studies support the validation of oncogenic B-Raf as a target for cancer therapy and provide the first evidence of a correlation between the expression of oncogenic BRAF alleles and a positive response to a selective B-Raf inhibitor. (Cancer Res 2006; 66(23): 11100-5)

Synergistic cytotoxicity of radiation and oncolytic Lister strain vaccinia in V600D/EBRAF mutant melanoma depends on JNK and TNF-α signaling

“…For example, the finding that approximately 50% of melanomas harbour oncogenic BRAF mutations has driven drug discovery programmes that have generated potent, selective inhibitors that are active against V600E BRAF mutant tumor cells (25)(26)(27). These agents have yielded dramatic results in clinical trials in patients with V600E BRAF mutant melanoma (28,29).…”

An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling

“…To identify potent inhibitors of dimeric BRAF, we compared eight structurally diverse RAF inhibitors: AZ-628 (AZ) (McDermott et al, 2007), TAK-632 (TAK) , LY3009120 (LY) (Peng et al, 2015), GDC-0879 (GDC) (Hoeflich et al, 2009), SB-590885 (SB) (King et al, 2006), PLX7904/Paradox Breaker (PB), which does not to induce paradoxical activation in wild-type BRAF cells , Vemurafenib (VEM) and Dabrafenib (DAB) (Rheault et al, 2013) (Figure S1A, Table S1). To compare potencies of inhibitors in cells endogenously expressing monomeric or dimeric BRAF V600E , we treated parental (PAR) SKMEL239 cells expressing full length BRAF V600E and the SKMEL239 derivative (clone C3) that is resistant to VEM due to enhanced dimerization of endogenous splice variants of BRAF V600E that lack the RAS-binding domain (Poulikakos et al, 2011).…”

Integrating BRAF/MEK inhibitors into combination therapy for melanoma

“…A number of more specific BRAF inhibitors have now been developed, some of which have relative selectivity for the BRAF V600E mutation compared with wild-type BRAF, such as SB590885 (GlaxoSmithKline, Collegeville, PA, USA) (King et al, 2006) and PLX-4032/PLX-4720 (Plexxikon, Berkley, CA, USA) (Tsai et al, 2008). As selective BRAF targeted compounds have relatively few off-target effects, it is now possible to assess the effects of specific pharmacological inhibition of BRAF in melanoma.…”