title: Discovery of novel 7-azaindoles as PDK1 inhibitors.
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.
authors.affiliation: Merck KGaA, Biopharma, Global Research & Development, Frankfurter Str. 250, D-64293 Darmstadt, Germany.
authors.forename: Margarita
authors.initials: M
authors.lastname: Wucherer-Plietker
authors.affiliation: Organisch-Chemisches Institut, Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 270, D-69120 Heidelberg, Germany.
authors.forename: Eugen
authors.initials: E
authors.lastname: Merkul
authors.affiliation: Organisch-Chemisches Institut, Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 270, D-69120 Heidelberg, Germany.
authors.forename: Thomas J J
authors.initials: TJJ
authors.lastname: Müller
authors.affiliation: Merck KGaA, Biopharma, Global Research & Development, Frankfurter Str. 250, D-64293 Darmstadt, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Esdar
authors.affiliation: Merck KGaA, Biopharma, Global Research & Development, Frankfurter Str. 250, D-64293 Darmstadt, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Knöchel
authors.affiliation: Merck KGaA, Biopharma, Global Research & Development, Frankfurter Str. 250, D-64293 Darmstadt, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Heinrich
authors.affiliation: Merck KGaA, Biopharma, Global Research & Development, Frankfurter Str. 250, D-64293 Darmstadt, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Buchstaller
authors.affiliation: Merck KGaA, Biopharma, Global Research & Development, Frankfurter Str. 250, D-64293 Darmstadt, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Greiner
authors.affiliation: Merck KGaA, Biopharma, Global Research & Development, Frankfurter Str. 250, D-64293 Darmstadt, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Dorsch
authors.affiliation: Merck KGaA, Biopharma, Global Research & Development, Frankfurter Str. 250, D-64293 Darmstadt, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Finsinger
authors.affiliation: Merck KGaA, Biopharma, Global Research & Development, Frankfurter Str. 250, D-64293 Darmstadt, Germany.
authors.forename: Michel
authors.initials: M
authors.lastname: Calderini
authors.affiliation: Merck KGaA, Biopharma, Global Research & Development, Frankfurter Str. 250, D-64293 Darmstadt, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Bruge
authors.affiliation: Merck KGaA, Biopharma, Global Research & Development, Frankfurter Str. 250, D-64293 Darmstadt, Germany. Electronic address: ulrich.graedler@merckgroup.com.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Grädler
mesh_terms: D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D013329:Structure-Activity Relationship
chemical_list: C023422:7-azaindole dimer; D007211:Indoles; C000631429:PDK1 protein, human; D047428:Protein Kinase Inhibitors; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017346:Protein Serine-Threonine Kinases
keywords: Fragment-screening; Kinase inhibitor; PDK1; Protein crystallography; Structure-based design; Virtual screening