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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

Journal Article · · Journal of Medicinal Chemistry
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  1. Eli Lilly and Company, Indianapolis, IN (United States)
  2. Deciphera Pharmaceuticals, LLC, Waltham, MA (United States)
  3. Emerald Biostructures, Bainbridge Island, WA (United States)
+ Show Author Affiliations

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 demonstrated 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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
Eli Lilly Company; USDOE Office of Science (SC)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1240168
Journal Information:
Journal of Medicinal Chemistry, Vol. 58, Issue 10; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 65 works
Citation information provided by
Web of Science

References (22)

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The CDK4/6 Inhibitor LY2835219 Overcomes Vemurafenib Resistance Resulting from MAPK Reactivation and Cyclin D1 Upregulation journal August 2014
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Kinase-Dead BRAF and Oncogenic RAS Cooperate to Drive Tumor Progression through CRAF journal January 2010
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Cited By (8)

New perspectives for targeting RAF kinase in human cancer journal October 2017
CRAF gene fusions in pediatric low-grade gliomas define a distinct drug response based on dimerization profiles journal August 2017
RAF inhibitor LY3009120 sensitizes RAS or BRAF mutant cancer to CDK4/6 inhibition by abemaciclib via superior inhibition of phospho-RB and suppression of cyclin D1 journal October 2017
Clinical responses to ERK inhibition in BRAF V600E-mutant colorectal cancer predicted using a computational model journal June 2017
A patent review of RAF kinase inhibitors (2010–2018) journal August 2019
KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer journal December 2017
BindingDB Entry 50046149: 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. dataset January 2016
Obatoclax and LY3009120 Efficiently Overcome Vemurafenib Resistance in Differentiated Thyroid Cancer journal January 2017

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