Aminoindazole PDK1 Inhibitors: A Case Study in Fragment-Based Drug Discovery

  • ACS Med Chem Lett. 2010 Jul 22;1(8):439-42. doi: 10.1021/ml100136n.
Jesús R Medina  1 ,  Charles W Blackledge  1 ,  Dirk A Heerding  1 ,  Nino Campobasso  2 ,  Paris Ward  2 ,  Jacques Briand  3 ,  Lois Wright  4 ,  Jeffrey M Axten  1
Affiliations
  • 1. Oncology Research, Signal Transduction DPU Medicinal Chemistry.
  • 2. Molecular Discovery Research, Computational and Structural Chemistry.
  • 3. Molecular Discovery Research, Analytical Chemistry.
  • 4. Molecular Discovery Research, Screening and Compound Profiling, GlaxoSmithKline, Research Triangle Park, North Carolina 27709.
PMID: 24900229 DOI: 10.1021/ml100136n
Abstract

Fragment screening of phosphoinositide-dependent kinase-1 (PDK1) in a biochemical kinase assay afforded hits that were characterized and prioritized based on ligand efficiency and binding interactions with PDK1 as determined by NMR. Subsequent crystallography and follow-up screening led to the discovery of aminoindazole 19, a potent leadlike PDK1 inhibitor with high ligand efficiency. Well-defined structure-activity relationships and protein crystallography provide a basis for further elaboration and optimization of 19 as a PDK1 inhibitor.

Keywords
Aminoindazole PDK1 inhibitors; binding interactions; fragment-based drug discovery; ligand efficiency.
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