Fragment-based design, synthesis, biological evaluation, and SAR of 1H-benzo[d]imidazol-2-yl)-1H-indazol derivatives as potent PDK1 inhibitors

Bioorg Med Chem Lett. 2017 Dec 15;27(24):5473-5480. doi: 10.1016/j.bmcl.2017.10.041. Epub 2017 Oct 28.

Abstract

In this work, we describe the use of the rule of 3 fragment-based strategies from biochemical screening data of 1100 in-house, small, low molecular weight fragments. The sequential combination of in silico fragment hopping and fragment linking based on S160/Y161/A162 hinge residues hydrogen bonding interactions leads to the identification of novel 1H-benzo[d]imidazol-2-yl)-1H-indazol class of Phosphoinositide-Dependent Kinase-1 (PDK1) inhibitors. Consequent SAR and follow-up screening data led to the discovery of two potent PDK1 inhibitors: compound 32 and 35, with an IC50 of 80 nM and 94 nM, respectively. Further biological evaluation showed that, at the low nanomolar concentration, the drug had potent ability to inhibit phosphorylation of AKT and p70S6, and selectively kill the cancer cells with mutations in both PTEN and PI3K. The microarray data showed that DUSP6, DUSP4, and FOSL1 were down-regulated in the sensitive cell lines with the compound treatment. The in vivo test showed that 35 can significantly inhibit tumor growth without influencing body weight growth. Our results suggest that these compounds, especially 35, merit further pre-clinical evaluation.

Keywords: 1H-benzo[d]imidazol-2-yl)-1H-indazoles; AN3-CA; DUSP4; DUSP6; FOSL1; Fragment-based design; KATO-III; MV4-11; PDK1 inhibitor.

MeSH terms

  • Apoptosis / drug effects
  • Binding Sites
  • Cell Line, Tumor
  • Down-Regulation / drug effects
  • Drug Design*
  • Dual Specificity Phosphatase 6 / genetics
  • Dual Specificity Phosphatase 6 / metabolism
  • Dual-Specificity Phosphatases / genetics
  • Dual-Specificity Phosphatases / metabolism
  • Humans
  • Imidazoles / chemistry
  • Indazoles / chemical synthesis
  • Indazoles / chemistry*
  • Indazoles / pharmacology
  • Inhibitory Concentration 50
  • Mitogen-Activated Protein Kinase Phosphatases / genetics
  • Mitogen-Activated Protein Kinase Phosphatases / metabolism
  • Molecular Docking Simulation
  • PTEN Phosphohydrolase / antagonists & inhibitors
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Structure-Activity Relationship

Substances

  • Imidazoles
  • Indazoles
  • PDK1 protein, human
  • Protein Kinase Inhibitors
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • RNA, Small Interfering
  • imidazole
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Mitogen-Activated Protein Kinase Phosphatases
  • DUSP4 protein, human
  • Dual Specificity Phosphatase 6
  • Dual-Specificity Phosphatases
  • PTEN Phosphohydrolase
  • PTEN protein, human