Design and synthesis of novel allosteric MEK inhibitor CH4987655 as an orally available anticancer agent

Bioorg Med Chem Lett. 2011 Mar 15;21(6):1795-801. doi: 10.1016/j.bmcl.2011.01.062. Epub 2011 Jan 21.


The MAP kinase pathway is one of the most important pathways involved in cell proliferation and differentiation, and its components are promising targets for antitumor drugs. Design and synthesis of a novel MEK inhibitor, based on the 3D-structural information of the target enzyme, and then multidimensional optimization including metabolic stability, physicochemical properties and safety profiles were effectively performed and led to the identification of a clinical candidate for an orally available potent MEK inhibitor, CH4987655, possessing a unique 3-oxo-oxazinane ring structure at the 5-position of the benzamide core structure. CH4987655 exhibits slow dissociation from the MEK enzyme, remarkable in vivo antitumor efficacy both in mono- and combination therapy, desirable metabolic stability, and insignificant MEK inhibition in mouse brain, implying few CNS-related side effects in human. An excellent PK profile and clear target inhibition in PBMC were demonstrated in a healthy volunteer clinical study.

MeSH terms

  • Administration, Oral
  • Allosteric Regulation
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Benzamides / administration & dosage
  • Benzamides / chemistry*
  • Benzamides / pharmacology
  • Humans
  • MAP Kinase Kinase Kinases / antagonists & inhibitors*
  • Models, Molecular
  • Oxazines / administration & dosage
  • Oxazines / chemistry*
  • Oxazines / pharmacology
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology


  • Antineoplastic Agents
  • Benzamides
  • CH 4987655
  • Oxazines
  • Protein Kinase Inhibitors
  • MAP Kinase Kinase Kinases