LXH254, a Potent and Selective ARAF-Sparing Inhibitor of BRAF and CRAF for the Treatment of MAPK-Driven Tumors

Purpose: Targeting RAF for antitumor therapy in RAS-mutant tumors holds promise. Herein, we describe at length novel qualities from the type II RAF inhibitor, LXH254.

Experimental design: LXH254 was profiled in biochemical, in vitro, as well as in vivo assays, including analyzing those activities from the drug inside a large panel of cancer-derived cell lines along with a comprehensive group of in vivo models. Additionally, activity of LXH254 was assessed in cells where different teams of RAF paralogs were ablated, or that expressed kinase-impaired and dimer-deficient variants of ARAF.

Results: We describe an unpredicted paralog selectivity of LXH254, which has the capacity to potently hinder BRAF and CRAF, but has less activity against ARAF. LXH254 was active in models harboring BRAF alterations, including atypical BRAF alterations coexpressed with mutant K/NRAS, and NRAS mutants, but had only modest activity in KRAS mutants. In RAS-mutant lines, lack of ARAF, although not BRAF or CRAF, sensitized cells to LXH254. ARAF-mediated potential to deal with LXH254 needed both kinase function and dimerization. Greater concentrations of LXH254 were needed to hinder signaling in RAS-mutant cells expressing only ARAF in accordance with BRAF or CRAF. Furthermore, particularly in cells expressing only ARAF, LXH254 caused paradoxical activation of MAPK signaling inside a manner much like dabrafenib. Finally, in vivo, LXH254 drove complete regressions of isogenic variants of RAS-mutant cells missing ARAF expression, while parental lines were only modestly sensitive.

Conclusions: LXH254 is really a novel RAF inhibitor, which Naporafenib has the capacity to hinder dimerized BRAF and CRAF, in addition to monomeric BRAF, while largely sparing ARAF.