Tovorafenib

Pediatric low-grade glioma, the most common childhood central nervous system (CNS) tumour, is often associated with BRAF genomic alterations, such as BRAF fusion or rearrangement. The BRAF kinase family is activated by RAS to phosphorylate MEK1/2, which phosphorylates ERK1/2 and promotes downstream signalling cascades that regulate multiple cellular processes, such as cell growth, proliferation, and differentiation. Oncogenic mutations in BRAF lead to an aberrant and hyperactivated RAS-RAF-MEK-ERK pathway, also known as the mitogen-activated protein kinase (MAPK) signalling pathway.

Several RAF kinase inhibitors have been developed to treat cancers with BRAF mutations. These RAF inhibitors have been categorized into different "types" depending on their selectivity to a BRAF isoform and binding modes. Tovorafenib is a Type II RAF kinase inhibitor. RAF has a conserved three-residue segment (Asp-Phe-Gly) located at the N-terminus of the kinase activation loop called a DFG motif. In a state called a “DGF-out” conformation, the DFG motif is flipped in a way that reorients the phenylalanine residue, leaving a vacant site in which the drug can extend from the ATP site to insert a hydrophobic group. Tovorafenib is active against mutant BRAF V600E, wild-type BRAF, and wild-type CRAF kinases. Tovorafenib exhibited antitumor activity in cultured cells and xenograft tumour models harbouring BRAF V600E and V600D mutations, and in a xenograft model harbouring a BRAF fusion. Tovorafenib is not reported to induce paradoxical activation of the MAPK pathway.