title: The discovery and optimization of aminooxadiazoles as potent Pim kinase inhibitors.
abstract: High levels of Pim expression have been implicated in several hematopoietic and solid tumor cancers. These findings suggest that inhibition of Pim signaling by a small molecule Pim-1,2 inhibitor could provide patients with therapeutic benefit. Herein, we describe our progress towards this goal starting from the highly Pim-selective indole-thiadiazole compound (1), which was derived from a nonselective hit identified in a high throughput screening campaign. Optimization of this compound's potency and its pharmacokinetic properties resulted in the discovery of compound 29. Cyclopropane 29 was found to exhibit excellent enzymatic potency on the Pim-1 and Pim-2 isoforms (Ki values of 0.55nM and 0.28nM, respectively), and found to inhibit the phosphorylation of BAD in the Pim-overexpressing KMS-12 cell line (IC50=150nM). This compound had moderate clearance and bioavailability in rat (CL=2.42L/kg/h; %F=24) and exhibited a dose-dependent inhibition of p-BAD in KMS-12 tumor pharmacodynamic (PD) model with an EC50 value of 6.74μM (18μg/mL) when dosed at 10, 30, 100 and 200mg/kg po in mice.
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA. Electronic address: rwurz@amgen.com.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Wurz
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Liping H
authors.initials: LH
authors.lastname: Pettus
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Claire
authors.initials: C
authors.lastname: Jackson
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Wu
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Wang
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Brad
authors.initials: B
authors.lastname: Herberich
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Cee
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Lanman
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Reed
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Chavez
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Nixey
authors.affiliation: Department of Discovery Technologies, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Laszlo
authors.affiliation: Department of Molecular Structure and Characterization, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Molecular Structure and Characterization, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Yen
authors.initials: Y
authors.lastname: Nguyen
authors.affiliation: Department of Oncology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Sastri
authors.affiliation: Department of Oncology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Nadia
authors.initials: N
authors.lastname: Guerrero
authors.affiliation: Department of Oncology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Winston
authors.affiliation: Department of Oncology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: J Russell
authors.initials: JR
authors.lastname: Lipford
authors.affiliation: Department of Molecular Structure and Characterization, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Lee
authors.affiliation: Department of Molecular Structure and Characterization, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Andrews
authors.affiliation: Department of Molecular Structure and Characterization, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Mohr
authors.affiliation: Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Pharmaceutics R&D, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Darren L
authors.initials: DL
authors.lastname: Reid
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Tasker
mesh_terms: D018360:Crystallography, X-Ray; D055808:Drug Discovery; D015394:Molecular Structure; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors*
chemical_list: D010069:Oxadiazoles; D047428:Protein Kinase Inhibitors; D051573:Proto-Oncogene Proteins c-pim-1
keywords: BAD phosphorylation; KMS-12; Multiple myeloma; Oxadiazole; Pim kinase inhibitor