Naporafenib

Naporafenib (LXH254) is a potent, selective, orally active, type II BRAF and CRAF inhibitor, with IC₅₀ values of 0.072 and 0.21 nM against CRAF and BRAF, respectively^[1][2]. IC50 & Target:CRAF, BRAF^[1] In Vitro:Naporafenib (Compound A) is an adenosine triphosphate (ATP)-competitive inhibitor of BRAF (also referred to herein as b-RAF or b-Raf) and CRAF (also referred to herein as c-RAF or c- Raf) protein kinases. Throughout the present disclosure, Naporafenib is also referred to as a c-RAF (or CRAF) inhibitor or a C-RAF/c-Raf kinase inhibitor. In cell-based assays, Naporafenib has demonstrated anti-proliferative activity in cell lines that contain a variety of mutations that activate MAPK signaling. Moreover, Naporafenib is a Type 2 ATP -competitive inhibitor of both B-Raf and C-Raf that keeps the kinase pocket in an inactive conformation, thereby reducing the paradoxical activation seen with many B-Raf inhibitors, and blocking mutant RAS-driven signaling and cell proliferation^[1].
Naporafenib (0-10 µM, 1 h) inhibits both monomeric and dimeric RAF and promotes RAF dimer formation^[2].
Naporafenib has reduced ability to suppress MAPK signaling driven by ARAF and further that the contribution of ARAF to MAPK signaling increases in the absence of CRAF expression^[2].
Naporafenib shows more sensitivity when cells lack ARAF^[2]. In Vivo:Treatment with Naporafenib (Compound A) generates tumor regression in several KRAS-mutant models including the NSCLC-derived Calu-6 (KRAS Q61K) and NCI-H358 (KRAS G12C). Naporafenib exhibits efficacy in numerous MAPK-driven human cancer cell lines and in xenograft tumors representing model tumors harboring human lesions in KRAS, NRAS and BRAF oncogenes^[1].
Naporafenib shows significant antitumor activity in models harboring BRAF mutations either alone or coincident with either activated NRAS or KRAS, and RAS mutants lacking ARAF are more sensitive to Naporafenib^[2].