Naporafenib (LXH-254)

Description: LXH254, extracted from patent WO2018051306A1, Compound A, is a novel, potent and orally bioavailable CRAF inhibitor, also is a potent BRAF inhibitor. LXH254 is a type II ATP-competitive inhibitor that inhibits both B- and CRAF kinase activities at picomolar concentrations with a high degree of selectivity against a panel of 456 human kinases and in cell-based assays. LXH254 not only inhibits MAPK signaling activity in tumor models harboring BRAFV600 mutation, but also inhibits mutant N- and KRAS-driven signaling due to its ability to inhibit both RAF monomers and dimers with similar potencies. LXH254 is orally bioavailable, demonstrates a direct PK/PD relationship and causes tumor regression in multiple cell line and primary human tumor derived xenograft models at well-tolerated doses. LXH254 represents a next generation RAF inhibitor that is differentiated from other RAF inhibitors in this class due to the high degree of selectivity. In preclinical efficacy and toxicology studies, LXH254 demonstrated a relatively wide therapeutic index which should enable effective interrogation of RAF inhibition in patients with decreased risk for off-target toxicity. LXH254 is currently in a Phase I trial in patients with solid tumors expressing MAPK pathway mutations. LXH254 inhibits all members of the serine/threonine protein kinase Raf family with potential antineoplastic activity. pan-RAF inhibitor LXH254 binds to Raf proteins and inhibits Raf-mediated signal transduction pathways. This inhibits proliferation of Raf-overexpressing tumor cells. Raf protein kinases are critical enzymes in the Ras/Raf/MEK/ERK signaling pathway and are upregulated in a variety of cancer cell types..

References: WO 2018051306 A1 20180322; https://cancerres.aacrjournals.org/content/78/13_Supplement/DDT01-04