Inhibition of RAF Isoforms and Active Dimers by LY3009120 Leads to Anti-tumor Activities in RAS or BRAF Mutant Cancers.
LY3009120 is a pan-RAF and RAF dimer inhibitor that inhibits all RAF isoforms and occupies both protomers in RAF dimers. Biochemical and cellular analyses revealed that LY3009120 inhibits ARAF, BRAF, and CRAF isoforms with similar affinity, while vemurafenib or dabrafenib have little or modest CRAF activity compared to their BRAF activities. LY3009120 induces BRAF-CRAF dimerization but inhibits the phosphorylation of downstream MEK and ERK, suggesting that it effectively inhibits the kinase activity of BRAF-CRAF heterodimers. Further analyses demonstrated that LY3009120 also inhibits various forms of RAF dimers including BRAF or CRAF homodimers. Due to these unique properties, LY3009120 demonstrates minimal paradoxical activation, inhibits MEK1/2 phosphorylation, and exhibits anti-tumor activities across multiple models carrying KRAS, NRAS, or BRAF mutation.
Eli Lilly and Company, Indianapolis, IN 46285, USA. Electronic address: peng_sheng-bin@lilly.com.
Sheng-Bin
SB
Peng
Eli Lilly and Company, Indianapolis, IN 46285, USA.
James R
JR
Henry
Deciphera Pharmaceuticals, LLC, Lawrence, KS 66044, USA.
Michael D
MD
Kaufman
Deciphera Pharmaceuticals, LLC, Lawrence, KS 66044, USA.
Wei-Ping
WP
Lu
Deciphera Pharmaceuticals, LLC, Lawrence, KS 66044, USA.
Bryan D
BD
Smith
Deciphera Pharmaceuticals, LLC, Lawrence, KS 66044, USA.
Subha
S
Vogeti
Deciphera Pharmaceuticals, LLC, Lawrence, KS 66044, USA.
Thomas J
TJ
Rutkoski
Deciphera Pharmaceuticals, LLC, Lawrence, KS 66044, USA.
Scott
S
Wise
Emerald Biostructures, Bainbridge Island, WA 98110, USA.
Lawrence
L
Chun
Eli Lilly and Company, Indianapolis, IN 46285, USA.
Youyan
Y
Zhang
Eli Lilly and Company, Indianapolis, IN 46285, USA.
Robert D
RD
Van Horn
Eli Lilly and Company, Indianapolis, IN 46285, USA.
Tinggui
T
Yin
Eli Lilly and Company, Indianapolis, IN 46285, USA.
Xiaoyi
X
Zhang
Eli Lilly and Company, Indianapolis, IN 46285, USA.
Vipin
V
Yadav
Eli Lilly and Company, Indianapolis, IN 46285, USA.
Shih-Hsun
SH
Chen
Eli Lilly and Company, Indianapolis, IN 46285, USA.
Xueqian
X
Gong
Eli Lilly and Company, Indianapolis, IN 46285, USA.
Xiwen
X
Ma
Eli Lilly and Company, Indianapolis, IN 46285, USA.
Yue
Y
Webster
Eli Lilly and Company, Indianapolis, IN 46285, USA.
Sean
S
Buchanan
Eli Lilly and Company, Indianapolis, IN 46285, USA.
Igor
I
Mochalkin
Eli Lilly and Company, Indianapolis, IN 46285, USA.
Lysiane
L
Huber
Eli Lilly and Company, Indianapolis, IN 46285, USA.
Lisa
L
Kays
Eli Lilly and Company, Indianapolis, IN 46285, USA.
Gregory P
GP
Donoho
Eli Lilly and Company, Indianapolis, IN 46285, USA.
Jennie
J
Walgren
Eli Lilly and Company, Indianapolis, IN 46285, USA.
Denis
D
McCann
Eli Lilly and Company, Indianapolis, IN 46285, USA.
Phenil
P
Patel
Eli Lilly and Company, Indianapolis, IN 46285, USA.
Ilaria
I
Conti
Eli Lilly and Company, Indianapolis, IN 46285, USA.
Gregory D
GD
Plowman
Eli Lilly and Company, Indianapolis, IN 46285, USA.
James J
JJ
Starling
Deciphera Pharmaceuticals, LLC, Lawrence, KS 66044, USA.
Daniel L
DL
Flynn
D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019281:Dimerization; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D020033:Protein Isoforms / Q000037:antagonists & inhibitors* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics*; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D018631:ras Proteins / Q000235:genetics*
D000970:Antineoplastic Agents; C000600963:LY3009120; D010671:Phenylurea Compounds; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins