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

J Med Chem. 2015 May 28;58(10):4165-79. doi: 10.1021/acs.jmedchem.5b00067. Epub 2015 May 12.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / 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
  • Phenylurea Compounds / chemistry*
  • Phenylurea Compounds / pharmacokinetics
  • Phenylurea Compounds / pharmacology*
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors
  • Proto-Oncogene Proteins B-raf / genetics*
  • Proto-Oncogene Proteins B-raf / metabolism
  • Proto-Oncogene Proteins c-raf / metabolism
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology*
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Xenograft Model Antitumor Assays
  • ras Proteins / genetics
  • ras Proteins / metabolism*

Substances

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