title: The discovery of novel 3-(pyrazin-2-yl)-1H-indazoles as potent pan-Pim kinase inhibitors.
abstract: The three Pim kinases are a small family of serine/threonine kinases regulating several signaling pathways that are fundamental to tumorigenesis. As such, the Pim kinases are a very attractive target for pharmacological inhibition in cancer therapy. Herein, we describe our efforts toward the development of a potent, pan-Pim inhibitor. The synthesis and hit-to-lead SAR development from a 3-(pyrazin-2-yl)-1H-indazole derived hit 2 to the identification of a series of potent, pan-Pim inhibitors such as 13o are described.
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA. Electronic address: huiw@amgen.com.
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. Electronic address: vcee@amgen.com.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Cee
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: 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: Bin
authors.initials: B
authors.lastname: Wu
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: J Russell
authors.initials: JR
authors.lastname: Lipford
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: Jeff
authors.initials: J
authors.lastname: Winston
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: Xin
authors.initials: X
authors.lastname: Huang
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: 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 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: D055808:Drug Discovery; D006801:Humans; D007191:Indazoles / Q000737:chemistry* / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D007191:Indazoles; D047428:Protein Kinase Inhibitors; D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim
keywords: Hematologic malignancy; KMS-12; Multiple myeloma; Pim kinase; pan Pim kinase inhibitor