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: James R Henry, Michael D Kaufman, Sheng-Bin Peng, Yu Mi Ahn, Timothy M Caldwell, Lakshminarayana Vogeti, Hanumaiah Telikepalli, Wei-Ping Lu, Molly M Hood, Thomas J Rutkoski, Bryan D Smith, Subha Vogeti, David Miller, Scott C Wise, Lawrence Chun, Xiaoyi Zhang, Youyan Zhang, Lisa Kays, Philip A Hipskind, Aaron D Wrobleski, Karen L Lobb, Julia M Clay, Jeffrey D Cohen, Jennie L Walgren, Denis McCann, Phenil Patel, David K Clawson, Sherry Guo, Danalyn Manglicmot, Chris Groshong, Cheyenne Logan, James J Starling, Daniel L Flynn
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 58 Issue 10 Pg. 4165-79 (May 28 2015) ISSN: 1520-4804 [Electronic] United States
• PMID: 25965804 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• LY3009120
• Phenylurea Compounds
• Pyrimidines
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• Proto-Oncogene Proteins c-raf
• ras Proteins

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacokinetics, pharmacology)
• Biological Availability
• Cell Line, Tumor (drug effects)
• Chemistry Techniques, Synthetic
• Dogs
• Female
• Half-Life
• Humans
• Male
• Mice, Nude
• Molecular Targeted Therapy
• Mutation
• Phenylurea Compounds (chemical synthesis, chemistry, pharmacokinetics, pharmacology)
• Proto-Oncogene Proteins B-raf (antagonists & inhibitors, genetics, metabolism)
• Proto-Oncogene Proteins c-raf (metabolism)
• Pyrimidines (chemical synthesis, chemistry, pharmacokinetics, pharmacology)
• Rats, Sprague-Dawley
• Structure-Activity Relationship
• Xenograft Model Antitumor Assays
• ras Proteins (genetics, metabolism)