Raf dimer inhibitors bind RAF heterodimers

Stable Identifier
Reaction [binding]
Homo sapiens
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LY3009120, TAK-580 and TAK-632 are pan-RAF inhibitors that binds to all 3 RAF isoforms as well as to RAF dimers to inhibit phosphorylation of MAP2K and MAPK proteins (Nakamura et al, 2013; Okaniwa et al, 2013; Sun et al, 2017; Peng et al, 2015; Henry et al, 2015; Vakana et al, 2017). Because they inhibit the kinase activity of RAF homo- and heterodimers, treatment with pan-RAF dimer inhibitors generates minimal paradoxical RAF activation and inhibits cellular proliferation in a number of tumor models (Peng et al, 2015; Henry et al, 2015, Vakana et al, 2017; reviewed in Karoulia et al, 2017; Agianian and Gavathiotis, 2018; ).

Literature References
PubMed ID Title Journal Year
23906342 Discovery of a selective kinase inhibitor (TAK-632) targeting pan-RAF inhibition: design, synthesis, and biological evaluation of C-7-substituted 1,3-benzothiazole derivatives

Kawamoto, T, Yano, J, Aertgeerts, K, Takagi, T, Tsutsumi, S, Tottori, T, Inui, Y, Sang, BC, Okaniwa, M, Ishikawa, T, Sumita, A, Yabuki, M, Uchiyama, N, Arita, T, Hirose, M, Yoshida, S, Nakamura, A

J. Med. Chem. 2013
28082416 A brain-penetrant RAF dimer antagonist for the noncanonical BRAF oncoprotein of pediatric low-grade astrocytomas

Hahn, WC, Sun, Y, Buhrlage, SJ, Mazzola, E, Stiles, CD, Ligon, KL, Ramkissoon, LA, Chadwick, EJ, Garraway, LA, Pilarz, C, Agar, NY, Yao, Z, Calligaris, D, Goumnerova, L, Segal, RA, Kieran, MW, Garcia, VM, Alberta, JA, Kane, M, Ramkissoon, SH, Gray, NS, Rosen, N

Neuro-oncology 2017
28984291 New perspectives for targeting RAF kinase in human cancer

Gavathiotis, E, Karoulia, Z, Poulikakos, PI

Nat. Rev. Cancer 2017
27999210 LY3009120, a panRAF inhibitor, has significant anti-tumor activity in BRAF and KRAS mutant preclinical models of colorectal cancer

Blosser, W, Vakana, E, Simpson, N, Stancato, LF, Huber, L, Zhang, Y, Dowless, M, Manro, J, Pratt, S, Jaken, S, Stephens, J, Yuan, XJ, Peng, SB

Oncotarget 2017
29461827 Current Insights of BRAF Inhibitors in Cancer

Gavathiotis, E, Agianian, B

J. Med. Chem. 2018
24121489 Antitumor activity of the selective pan-RAF inhibitor TAK-632 in BRAF inhibitor-resistant melanoma

Tsuchiya, S, Okaniwa, M, Ishikawa, T, Donelan, J, Carideo, E, Arita, T, Yoshida, S, Chouitar, J, Galvin, K, Nakamura, A

Cancer Res. 2013
25965804 Discovery of 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (LY3009120) as a pan-RAF inhibitor with minimal paradoxical activation and activity against BRAF or RAS mutant tumor cells

Hood, MM, Groshong, C, Clay, JM, Caldwell, TM, Ahn, YM, Clawson, DK, Walgren, JL, Miller, D, Hipskind, PA, Guo, S, McCann, D, Wise, SC, Cohen, JD, Manglicmot, D, Logan, C, Peng, SB, Vogeti, L, Telikepalli, H, Wrobleski, AD, Lobb, KL, Rutkoski, TJ, Vogeti, S, Smith, BD, Flynn, DL, Kays, L, Patel, P, Zhang, Y, Chun, L, Lu, WP, Kaufman, MD, Starling, JJ, Zhang, X, Henry, JR

J. Med. Chem. 2015
26343583 Inhibition of RAF Isoforms and Active Dimers by LY3009120 Leads to Anti-tumor Activities in RAS or BRAF Mutant Cancers

McCann, D, Huber, L, Peng, SB, Webster, Y, Buchanan, S, Plowman, GD, Rutkoski, TJ, Vogeti, S, Smith, BD, Yadav, V, Flynn, DL, Ma, X, Kays, L, Patel, P, Yin, T, Zhang, Y, Chun, L, Walgren, J, Lu, WP, Gong, X, Kaufman, MD, Starling, JJ, Conti, I, Wise, S, Zhang, X, Van Horn, RD, Donoho, GP, Chen, SH, Mochalkin, I, Henry, JR

Cancer Cell 2015
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