8F7P

BRAF kinase in complex with LXH254 (naporafenib)

Summary for 8F7P

• Entry DOI: 10.2210/pdb8f7p/pdb
• Descriptor: Serine/threonine-protein kinase B-raf, N-{3-[2-(2-hydroxyethoxy)-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl}-2-(trifluoromethyl)pyridine-4-carboxamide (3 entities in total)
• Functional Keywords: braf, lxh254, naporafenib, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 65034.34

Authors

Tkacik, E.,Li, K.,Gonzalez Del-Pino, G.,Eck, M.J. (deposition date: 2022-11-20, release date: 2023-04-12, Last modification date: 2024-05-22)

Primary citation

Tkacik, E.,Li, K.,Gonzalez-Del Pino, G.,Ha, B.H.,Vinals, J.,Park, E.,Beyett, T.S.,Eck, M.J.
Structure and RAF family kinase isoform selectivity of type II RAF inhibitors tovorafenib and naporafenib.
J.Biol.Chem., 299:104634-104634, 2023

PubMed Abstract: Upon activation by RAS, RAF family kinases initiate signaling through the MAP kinase cascade to control cell growth, proliferation, and differentiation. Among RAF isoforms (ARAF, BRAF, and CRAF), oncogenic mutations are by far most frequent in BRAF. The BRAF mutation drives more than half of all malignant melanoma and is also found in many other cancers. Selective inhibitors of BRAF (vemurafenib, dabrafenib, encorafenib) are used clinically for these indications, but they are not effective inhibitors in the context of oncogenic RAS, which drives dimerization and activation of RAF, nor for malignancies driven by aberrantly dimerized truncation/fusion variants of BRAF. By contrast, a number of "type II" RAF inhibitors have been developed as potent inhibitors of RAF dimers. Here, we compare potency of type II inhibitors tovorafenib (TAK-580) and naporafenib (LHX254) in biochemical assays against the three RAF isoforms and describe crystal structures of both compounds in complex with BRAF. We find that tovorafenib and naporafenib are most potent against CRAF but markedly less potent against ARAF. Crystal structures of both compounds with BRAF or WT BRAF reveal the details of their molecular interactions, including the expected type II-binding mode, with full occupancy of both subunits of the BRAF dimer. Our findings have important clinical ramifications. Type II RAF inhibitors are generally regarded as pan-RAF inhibitors, but our studies of these two agents, together with recent work with type II inhibitors belvarafenib and naporafenib, indicate that relative sparing of ARAF may be a property of multiple drugs of this class.

PubMed: 36963492
DOI: 10.1016/j.jbc.2023.104634

Experimental method

X-RAY DIFFRACTION (2.74 Å)