Inhibition of RAF Isoforms and Active Dimers by LY3009120 Leads to Anti-tumor Activities in RAS or BRAF Mutant Cancers

Sheng-Bin Peng; James R Henry; Michael D Kaufman; Wei-Ping Lu; Bryan D Smith; Subha Vogeti; Thomas J Rutkoski; Scott Wise; Lawrence Chun; Youyan Zhang; Robert D Van Horn; Tinggui Yin; Xiaoyi Zhang; Vipin Yadav; Shih-Hsun Chen; Xueqian Gong; Xiwen Ma; Yue Webster; Sean Buchanan; Igor Mochalkin; Lysiane Huber; Lisa Kays; Gregory P Donoho; Jennie Walgren; Denis McCann; Phenil Patel; Ilaria Conti; Gregory D Plowman; James J Starling; Daniel L Flynn

doi:10.1016/j.ccell.2015.08.002

Inhibition of RAF Isoforms and Active Dimers by LY3009120 Leads to Anti-tumor Activities in RAS or BRAF Mutant Cancers

Cancer Cell. 2015 Sep 14;28(3):384-98. doi: 10.1016/j.ccell.2015.08.002. Epub 2015 Sep 3.

Authors

Sheng-Bin Peng¹, James R Henry², Michael D Kaufman³, Wei-Ping Lu³, Bryan D Smith³, Subha Vogeti³, Thomas J Rutkoski³, Scott Wise³, Lawrence Chun⁴, Youyan Zhang², Robert D Van Horn², Tinggui Yin², Xiaoyi Zhang², Vipin Yadav², Shih-Hsun Chen², Xueqian Gong², Xiwen Ma², Yue Webster², Sean Buchanan², Igor Mochalkin², Lysiane Huber², Lisa Kays², Gregory P Donoho², Jennie Walgren², Denis McCann², Phenil Patel², Ilaria Conti², Gregory D Plowman², James J Starling², Daniel L Flynn³

Affiliations

¹ Eli Lilly and Company, Indianapolis, IN 46285, USA. Electronic address: peng_sheng-bin@lilly.com.
² Eli Lilly and Company, Indianapolis, IN 46285, USA.
³ Deciphera Pharmaceuticals, LLC, Lawrence, KS 66044, USA.
⁴ Emerald Biostructures, Bainbridge Island, WA 98110, USA.

PMID: 26343583
DOI: 10.1016/j.ccell.2015.08.002

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Dimerization
Humans
MAP Kinase Signaling System / drug effects
MAP Kinase Signaling System / genetics
Mitogen-Activated Protein Kinases / genetics
Mutation / drug effects
Mutation / genetics
Neoplasms / drug therapy*
Neoplasms / genetics
Phenylurea Compounds / pharmacology*
Phosphorylation / drug effects
Phosphorylation / genetics
Protein Isoforms / antagonists & inhibitors*
Protein Isoforms / genetics
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
Proto-Oncogene Proteins B-raf / genetics*
Proto-Oncogene Proteins c-raf / genetics
Pyrimidines / pharmacology*
Signal Transduction / drug effects
Signal Transduction / genetics
ras Proteins / genetics*

Substances

Antineoplastic Agents
LY3009120
Phenylurea Compounds
Protein Isoforms
Protein Kinase Inhibitors
Pyrimidines
BRAF protein, human
Proto-Oncogene Proteins B-raf
Proto-Oncogene Proteins c-raf
Mitogen-Activated Protein Kinases
ras Proteins