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Antiproliferative effect of RAF709 compared to dabrafenib, trametinib, RAF265 and sorafenib across a tumor cell panel

Legends for supplemental figures and tables

Table S1: Kinase hits from KinomeScan panel. Table S4: Antiproliferative activity of RAF709 in a Ba/F3 cell kinase panel.

Resistance to the RAF inhibitor vemurafenib arises commonly in melanomas driven by the activated BRAF oncogene. Here, we report antitumor properties of RAF709, a novel ATP-competitive kinase inhibitor with high potency and selectivity against RAF kinases. RAF709 exhibited a mode of RAF inhibition distinct from RAF monomer inhibitors such as vemurafenib, showing equal activity against both RAF monomers and dimers. As a result, RAF709 inhibited MAPK signaling activity in tumor models harboring either BRAFV600 alterations or mutant N- and KRAS-driven signaling, with minimal paradoxical activation of wild-type RAF. In cell lines and murine xenograft models, RAF709 demonstrated selective antitumor activity in tumor cells harboring BRAF or RAS mutations compared with cells with wild-type BRAF and RAS genes. RAF709 demonstrated a direct pharmacokinetic/pharmacodynamic relationship in in vivo tumor models harboring KRAS mutation. Furthermore, RAF709 elicited regression of primary human tumor–derived xenograft models with BRAF, NRAS, or KRAS mutations with excellent tolerability. Our results support further development of inhibitors like RAF709, which represents a next-generation RAF inhibitor with unique biochemical and cellular properties that enables antitumor activities in RAS-mutant tumors.Significance: In an effort to develop RAF inhibitors with the appropriate pharmacological properties to treat RAS mutant tumors, RAF709, a compound with potency, selectivity, and in vivo properties, was developed that will allow preclinical therapeutic hypothesis testing, but also provide an excellent probe to further unravel the complexities of RAF kinase signaling. Cancer Res; 78(6); 1537–48. ©2018 AACR.

Figure S1: pMEK and pERK suppression in KRAS mutant and BRAFV600E cells by dabrafenib or RAF709. Figure S2: pMEK and pERK suppression in NRAS mutant and BRAFV600E cells by dabrafenib or RAF709. Figure S3: Cell cycle and apoptotic effects of RAF709 in KRASmut cells. Figure S4: Antiproliferative activity of RAF709 in HPAFII cells.