5HKM

DISCOVERY OF NOVEL 7-AZAINDOLES AS PDK1 INHIBITORS

Summary for 5HKM

• Entry DOI: 10.2210/pdb5hkm/pdb
• Descriptor: 3-phosphoinositide-dependent protein kinase 1, SULFATE ION, 4-ethyl-6-[5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-2-amine, ... (4 entities in total)
• Functional Keywords: pdk1 inhibitor, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: O15530
• Total number of polymer chains: 1
• Total formula weight: 35925.07

Authors

Wucherer-Plietker, M.,Esdar, C.,Knoechel, T.,Hillertz, P.,Heinrich, T.,Buchstaller, H.P.,Greiner, H.,Dorsch, D.,Calderini, M.,Bruge, D.,Mueller, T.J.J.,Graedler, U. (deposition date: 2016-01-14, release date: 2016-06-08, Last modification date: 2024-10-23)

Primary citation

Wucherer-Plietker, M.,Merkul, E.,Muller, T.J.,Esdar, C.,Knochel, T.,Heinrich, T.,Buchstaller, H.P.,Greiner, H.,Dorsch, D.,Finsinger, D.,Calderini, M.,Bruge, D.,Gradler, U.
Discovery of novel 7-azaindoles as PDK1 inhibitors.
Bioorg.Med.Chem.Lett., 26:3073-3080, 2016

PubMed Abstract: A combined screening strategy using HTS together with focused kinase library and virtual screening led to the identification of diverse chemical series as PDK1 inhibitors. We focused our medicinal chemistry efforts on 7-azaindoles with low micromolar IC50s (e.g., 16: IC50=1.1μM) in the biochemical PDK1 assay. Our structure-guided optimization efforts considered also PDK1 X-ray structures with weaker binding fragments and resulted in 7-azaindoles with significantly improved biochemical PDK1 potency in the two-digit nanomolar range. However, the most potent analogues only showed moderate activities in a cellular mechanistic assay (42: IC50=2.3μM) together with either low microsomal stability or low permeability. The described structure-activity relationship together with PDK1 X-ray structures and early ADME data provided the basis for our subsequent hit-to-lead program.

PubMed: 27217002
DOI: 10.1016/j.bmcl.2016.05.005

Experimental method

X-RAY DIFFRACTION (2.1 Å)