title: 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.
abstract: The RAS-RAF-MEK-MAPK cascade is an essential signaling pathway, with activation typically mediated through cell surface receptors. The kinase inhibitors vemurafenib and dabrafenib, which target oncogenic BRAF V600E, have shown significant clinical efficacy in melanoma patients harboring this mutation. Because of paradoxical pathway activation, both agents were demonstrated to promote growth and metastasis of tumor cells with RAS mutations in preclinical models and are contraindicated for treatment of cancer patients with BRAF WT background, including patients with KRAS or NRAS mutations. In order to eliminate the issues associated with paradoxical MAPK pathway activation and to provide therapeutic benefit to patients with RAS mutant cancers, we sought to identify a compound not only active against BRAF V600E but also wild type BRAF and CRAF. On the basis of its superior in vitro and in vivo profile, compound 13 was selected for further development and is currently being evaluated in phase I clinical studies.
authors.affiliation: †Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: James R
authors.initials: JR
authors.lastname: Henry
authors.affiliation: ‡Deciphera Pharmaceuticals, LLC, Waltham, Massachusetts 02451, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Kaufman
authors.affiliation: †Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Sheng-Bin
authors.initials: SB
authors.lastname: Peng
authors.affiliation: ‡Deciphera Pharmaceuticals, LLC, Waltham, Massachusetts 02451, United States.
authors.forename: Yu Mi
authors.initials: YM
authors.lastname: Ahn
authors.affiliation: ‡Deciphera Pharmaceuticals, LLC, Waltham, Massachusetts 02451, United States.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Caldwell
authors.affiliation: ‡Deciphera Pharmaceuticals, LLC, Waltham, Massachusetts 02451, United States.
authors.forename: Lakshminarayana
authors.initials: L
authors.lastname: Vogeti
authors.affiliation: ‡Deciphera Pharmaceuticals, LLC, Waltham, Massachusetts 02451, United States.
authors.forename: Hanumaiah
authors.initials: H
authors.lastname: Telikepalli
authors.affiliation: ‡Deciphera Pharmaceuticals, LLC, Waltham, Massachusetts 02451, United States.
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Lu
authors.affiliation: ‡Deciphera Pharmaceuticals, LLC, Waltham, Massachusetts 02451, United States.
authors.forename: Molly M
authors.initials: MM
authors.lastname: Hood
authors.affiliation: ‡Deciphera Pharmaceuticals, LLC, Waltham, Massachusetts 02451, United States.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rutkoski
authors.affiliation: ‡Deciphera Pharmaceuticals, LLC, Waltham, Massachusetts 02451, United States.
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Smith
authors.affiliation: ‡Deciphera Pharmaceuticals, LLC, Waltham, Massachusetts 02451, United States.
authors.forename: Subha
authors.initials: S
authors.lastname: Vogeti
authors.affiliation: ‡Deciphera Pharmaceuticals, LLC, Waltham, Massachusetts 02451, United States.
authors.forename: David
authors.initials: D
authors.lastname: Miller
authors.affiliation: ‡Deciphera Pharmaceuticals, LLC, Waltham, Massachusetts 02451, United States.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Wise
authors.affiliation: §Emerald Biostructures, Bainbridge Island, Washington 98110, United States.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chun
authors.affiliation: †Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Zhang
authors.affiliation: †Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Youyan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: †Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Lisa
authors.initials: L
authors.lastname: Kays
authors.affiliation: †Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Hipskind
authors.affiliation: †Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Wrobleski
authors.affiliation: †Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Lobb
authors.affiliation: †Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Clay
authors.affiliation: †Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Cohen
authors.affiliation: †Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Jennie L
authors.initials: JL
authors.lastname: Walgren
authors.affiliation: †Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Denis
authors.initials: D
authors.lastname: McCann
authors.affiliation: †Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Phenil
authors.initials: P
authors.lastname: Patel
authors.affiliation: †Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: David K
authors.initials: DK
authors.lastname: Clawson
authors.affiliation: †Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Sherry
authors.initials: S
authors.lastname: Guo
authors.affiliation: †Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Danalyn
authors.initials: D
authors.lastname: Manglicmot
authors.affiliation: †Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Chris
authors.initials: C
authors.lastname: Groshong
authors.affiliation: †Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Cheyenne
authors.initials: C
authors.lastname: Logan
authors.affiliation: †Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: James J
authors.initials: JJ
authors.lastname: Starling
authors.affiliation: ‡Deciphera Pharmaceuticals, LLC, Waltham, Massachusetts 02451, United States.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Flynn
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D045744:Cell Line, Tumor / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D004285:Dogs; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009154:Mutation; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C000600963:LY3009120; D010671:Phenylurea Compounds; D011743:Pyrimidines; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; D018631:ras Proteins