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PDBsum entry 4xv3
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Transferase/transferase inhibitor
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PDB id
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4xv3
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References listed in PDB file
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Key reference
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Title
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Raf inhibitors that evade paradoxical mapk pathway activation.
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Authors
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C.Zhang,
W.Spevak,
Y.Zhang,
E.A.Burton,
Y.Ma,
G.Habets,
J.Zhang,
J.Lin,
T.Ewing,
B.Matusow,
G.Tsang,
A.Marimuthu,
H.Cho,
G.Wu,
W.Wang,
D.Fong,
H.Nguyen,
S.Shi,
P.Womack,
M.Nespi,
R.Shellooe,
H.Carias,
B.Powell,
E.Light,
L.Sanftner,
J.Walters,
J.Tsai,
B.L.West,
G.Visor,
H.Rezaei,
P.S.Lin,
K.Nolop,
P.N.Ibrahim,
P.Hirth,
G.Bollag.
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Ref.
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Nature, 2015,
526,
583-586.
[DOI no: ]
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PubMed id
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Abstract
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Oncogenic activation of BRAF fuels cancer growth by constitutively promoting
RAS-independent mitogen-activated protein kinase (MAPK) pathway signalling.
Accordingly, RAF inhibitors have brought substantially improved personalized
treatment of metastatic melanoma. However, these targeted agents have also
revealed an unexpected consequence: stimulated growth of certain cancers.
Structurally diverse ATP-competitive RAF inhibitors can either inhibit or
paradoxically activate the MAPK pathway, depending whether activation is by BRAF
mutation or by an upstream event, such as RAS mutation or receptor tyrosine
kinase activation. Here we have identified next-generation RAF inhibitors
(dubbed 'paradox breakers') that suppress mutant BRAF cells without activating
the MAPK pathway in cells bearing upstream activation. In cells that express the
same HRAS mutation prevalent in squamous tumours from patients treated with RAF
inhibitors, the first-generation RAF inhibitor vemurafenib stimulated in vitro
and in vivo growth and induced expression of MAPK pathway response genes; by
contrast the paradox breakers PLX7904 and PLX8394 had no effect. Paradox
breakers also overcame several known mechanisms of resistance to
first-generation RAF inhibitors. Dissociating MAPK pathway inhibition from
paradoxical activation might yield both improved safety and more durable
efficacy than first-generation RAF inhibitors, a concept currently undergoing
human clinical evaluation with PLX8394.
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