title: A crystallographic fragment screen identifies cinnamic acid derivatives as starting points for potent Pim-1 inhibitors.
abstract: A crystallographic fragment screen was carried out to identify starting points for the development of inhibitors of protein kinase Pim-1, a potential target for tumour therapy. All fragment hits identified via soaking in this study turned out to bind to the unusually hydrophobic pocket at the hinge region. The most potent fragments, two cinnamic acid derivatives (with a best IC(50) of 130 µM), additionally form a well defined hydrogen bond. The balance between hydrophobic and polar interactions makes these molecules good starting points for further optimization. Pim-2 inhibitors from a recently reported high-throughput screening campaign also feature a cinnamic acid moiety. Two of these Pim-2 inhibitors were synthesized, their potencies against Pim-1 were determined and their cocrystal structures were elucidated in order to determine to what degree the binding modes identified by fragment screening are conserved in optimized inhibitors. The structures show that the cinnamic acid moieties indeed adopt the same binding mode. Fragment screening thus correctly identified binding modes which are maintained when fragments are grown into larger and higher affinity inhibitors. The high-throughput screening-derived compound (E)-3-{3-[6-(4-aminocyclohexylamino)-pyrazin-2-yl]phenyl}acrylic acid (compound 1) is the most potent inhibitor of the cinnamic acid series for which the three-dimensional binding mode is known (IC(50) = 17 nM, K(d) = 28 nM). The structure reveals the molecular basis for the large gain in potency between the initial fragment hit and this optimized inhibitor.
authors.affiliation: Bayer Schering Pharma AG, Global Drug Discovery, Berlin, Germany.
authors.forename: Michèle N
authors.initials: MN
authors.lastname: Schulz
authors.forename: Jörg
authors.initials: J
authors.lastname: Fanghänel
authors.forename: Martina
authors.initials: M
authors.lastname: Schäfer
authors.forename: Volker
authors.initials: V
authors.lastname: Badock
authors.forename: Hans
authors.initials: H
authors.lastname: Briem
authors.forename: Ulf
authors.initials: U
authors.lastname: Boemer
authors.forename: Duy
authors.initials: D
authors.lastname: Nguyen
authors.forename: Manfred
authors.initials: M
authors.lastname: Husemann
authors.forename: Roman C
authors.initials: RC
authors.lastname: Hillig
mesh_terms: D002934:Cinnamates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D018360:Crystallography, X-Ray; D020128:Inhibitory Concentration 50; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D002934:Cinnamates; D008024:Ligands; D047428:Protein Kinase Inhibitors; D051573:Proto-Oncogene Proteins c-pim-1