title: Structure-based design of low-nanomolar PIM kinase inhibitors.
abstract: PIM kinases are implicated in variety of cancers by promoting cell survival and proliferation and are targets of interest for therapeutic intervention. We have identified a low-nanomolar pan-PIM inhibitor (PIM1/2/3 potency 5:14:2nM) using structure based modeling. The crystal structure of this compound with PIM1 confirmed the predicted binding mode and protein-ligand interactions except those in the acidic ribose pocket. We show the SAR suggesting the importance of having a hydrogen bond donor in this pocket for inhibiting PIM2; however, this interaction is not important for inhibiting PIM1 or PIM3. In addition, we report the discovery of a new class of PIM inhibitors by using computational de novo design tool implemented in MOE software (Chemical Computing Group). These inhibitors have a different interaction profile.
authors.affiliation: Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142, USA. Electronic address: al_ishchenko@yahoo.com.
authors.forename: Alexey
authors.initials: A
authors.lastname: Ishchenko
authors.affiliation: Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Le Brazidec
authors.affiliation: Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Junhua
authors.initials: J
authors.lastname: Fan
authors.affiliation: Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Jer Hong
authors.initials: JH
authors.lastname: Chong
authors.affiliation: Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Aparna
authors.initials: A
authors.lastname: Hingway
authors.affiliation: Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Annie
authors.initials: A
authors.lastname: Raditsis
authors.affiliation: Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Latika
authors.initials: L
authors.lastname: Singh
authors.affiliation: Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142, USA; EMD Serono Research and Development Institute, 45A Middlesex Turnpike, Billerica, MA 01821, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Elenbaas
authors.affiliation: Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142, USA; Department of Chemistry, Keimyung University, 1095 Dalgubeoldaero, Dalseo-Gu, Daegu 704-701, Republic of Korea.
authors.forename: Victor Sukbong
authors.initials: VS
authors.lastname: Hong
authors.affiliation: Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Doug
authors.initials: D
authors.lastname: Marcotte
authors.affiliation: Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Silvian
authors.affiliation: Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Istvan
authors.initials: I
authors.lastname: Enyedy
authors.affiliation: Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Chao
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055672:Static Electricity; D013329:Structure-Activity Relationship
chemical_list: D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim
keywords: De novo design; Kinase inhibitors; PIM; PIM inhibitors; Rational design