The sulfamide moiety affords higher inhibitory activity and oral bioavailability to a series of coumarin dual selective RAF/MEK inhibitors

Bioorg Med Chem Lett. 2013 Dec 1;23(23):6223-7. doi: 10.1016/j.bmcl.2013.10.001. Epub 2013 Oct 9.


Introducing a sulfamide moiety to our coumarin derivatives afforded enhanced Raf/MEK inhibitory activity concomitantly with an acceptable PK profile. Novel sulfamide 17 showed potent HCT116 cell growth inhibition (IC50=8 nM) and good PK profile (bioavailability of 51% in mouse), resulting in high in vivo antitumor efficacy in the HCT116 xenograft (ED50=4.8 mg/kg). We confirmed the sulfamide moiety showed no negative impact on tests run on the compound to evaluate DMPK (PK profiles in three animal species, CYP inhibition and CYP induction) and the safety profile (hERG and AMES tests). Sulfamide 17 had favorable properties that warranted further preclinical assessment.

Keywords: 2-hydroxypropyl-β-cyclodextrin; Anticancer; ERK; HPCD; Kinase inhibitor; LYSA; MEK; PAMPA; PEG; Raf; Sulfamide; TGI; extracellular signal-regulated kinase; hERG; human ether-a-go-go related gene; lyophilized solubility assay; mitogen-activated protein kinase; parallel artificial membrane permeability assay; polyethylene glycol; tumor growth inhibition.

MeSH terms

  • Amides / chemistry
  • Amides / pharmacokinetics
  • Amides / pharmacology
  • Animals
  • Biological Availability
  • Coumarins / chemistry*
  • Coumarins / pharmacokinetics
  • Coumarins / pharmacology*
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Haplorhini
  • Mice
  • Protein Kinase Inhibitors / pharmacology*
  • Rats
  • Structure-Activity Relationship
  • Sulfonic Acids / chemistry
  • Sulfonic Acids / pharmacokinetics
  • Sulfonic Acids / pharmacology
  • Xenograft Model Antitumor Assays
  • raf Kinases / antagonists & inhibitors*
  • raf Kinases / metabolism


  • Amides
  • Coumarins
  • Protein Kinase Inhibitors
  • Sulfonic Acids
  • raf Kinases
  • Extracellular Signal-Regulated MAP Kinases