Reactome | Raf dimer inhibitors bind RAF heterodimers

Raf dimer inhibitors bind RAF heterodimers

Stable Identifier

R-HSA-9653108

Type

Reaction [binding]

Species

Homo sapiens

Compartment

plasma membrane, cytosol

ReviewStatus

5/5

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Raf dimer inhibitors bind RAF heterodimers

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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