A brain-penetrant RAF dimer antagonist for the noncanonical BRAF oncoprotein of pediatric low-grade astrocytomas

作者：Sun Yu; Alberta John A; Pilarz Catherine; Calligaris David; Chadwick Emily J; Ramkissoon Shakti H; Ramkissoon Lori A; Garcia Veronica Matia; Mazzola Emanuele; Goumnerova Liliana; Kane Michael; Yao Zhan; Kieran Mark W; Ligon Keith L; Hahn William C; Garraway Levi A; Rosen Neal; Gray Nathanael S; Agar Nathalie Y^*; Buhrlage Sara J^*; Segal Rosalind A^*; Stiles Charles D^*

来源：Neuro-Oncology, 2017, 19(6): 774-785.

DOI：10.1093/neuonc/now261

• MLN2480
• pediatric low-grade astrocytoma
• RAF dimers

Background. Activating mutations or structural rearrangements in BRAF are identified in roughly 75% of all pediatric low-grade astrocytomas (PLGAs). However, first-generation RAF inhibitors approved for adult melanoma have poor blood-brain penetrance and are only effective on tumors that express the canonical BRAFV600E oncoprotein, which functions as a monomer. These drugs (type I antagonists that target the "DFG-in" conformation of the kinase) fail to block signaling via KIAA1549: BRAF, a truncation/fusion BRAF oncoprotein which functions as a dimer and is found in the most common form of PLGA.
Methods. A panel of small molecule RAF inhibitors (including type II inhibitors, targeting the "DFG-out" conformation of the kinase) was screened for drugs showing efficacy on murine models of PLGA and on authentic human PLGA cells expressing KIAA1549: BRAF.
Results. We identify a type II RAF inhibitor that serves as an equipotent antagonist of BRAFV600E, KIAA1549: BRAF, and other noncanonical BRAF oncoproteins that function as dimers. This drug (MLN2480, also known as TAK-580) has good brain penetrance and is active on authentic human PLGA cells in brain organotypic cultures.
Conclusion. MLN2480 may be an effective therapeutic for BRAF mutant pediatric astrocytomas.

• 出版日期2017-6