2. Academic Validation
  3. Aminoindazole PDK1 Inhibitors: A Case Study in Fragment-Based Drug Discovery

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

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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